Compositions and methods for treating inflammatory conditions

ABSTRACT

The present invention relates to compositions containing signal transduction modulator compounds, to methods for treating or preventing inflammation, or promoting healthy joints, using the compounds and to kits for the same.

CROSS REFERENCE TO RELATED APPLICATION

This application claims the benefit of priority of U.S. patentapplication Ser. No. 11/151,174 filed Jun. 13, 2005, which is herebyincorporated by reference in its entirety.

FIELD OF THE PRESENT INVENTION

The present invention relates to compositions containing signaltransduction modulator compounds, to methods for treating and preventinginflammation using the compounds, and to a method for preparing thecompositions.

BACKGROUND OF THE PRESENT INVENTION

Inflammation often is a bodily response to infection or injury in whichcells involved in detoxification and repair are mobilized to thecompromised site by inflammatory mediators. The infection or injury canbe a result of acute or chronic disease, disorders, conditions ortrauma, environmental conditions, or aging. Examples of diseases,disorders, including autoimmune disorders, conditions, includingenvironmental conditions, or trauma, in which inflammation plays, or isthought to play a role, include diseases, disorders, syndromes,conditions and injuries of the cardiovascular, digestive, integumentary,muscular, nervous, reproductive, respiratory and urinary systems, aswell as, diseases, disorders, syndromes, conditions and injuries oftissue and cartilage such as atherosclerosis, Irritable Bowel Syndrome(IBS), psoriasis, tendonitis, Alzheimer's disease and vascular dementia,multiple sclerosis, diabetes, endometriosis, asthma and kidney failure.

The body's response to inflammation can include various symptoms,including edema, vasodilation, fever and pain, amongst others. Forexample, when inflammation is localized to joints, swelling of the jointlining, wearing down of cartilage and stiffening of the joints mayoccur. Thus, inflammation involving joints can be linked to a wide rangeof underlying joint conditions, from sprains to conditions collectivelyreferred to as “arthritis,” including rheumatoid arthritis. Suchinflammation often is associated with autoimmune disorders.

When inflammation is localized to the lungs, symptoms such as swellingand narrowing of the lining of the airways (i.e., bronchial tubes,bronchi) may occur, resulting in constriction of the airways. Theinflammation can stimulate production of mucous (sputum), which cancause further obstruction of the airways. Inflammation of the airways isassociated with a number of diseases, disorders and conditions. Forexample, allergic asthma, a disease linked to inflammation of theairways, is thought to be caused by an exaggerated response of theimmune system to harmless allergens (e.g., the house dust mite)resulting in a typical infiltration of the airway walls and injury anddesquamation of the airway epithelium by e.g., activated eosinophils andlymphocytes. Other types of asthma are provoked by factors including,but not limited to, vigorous exercise, irritant particles, andpsychologic stresses. While asthma often is chronic, the inflammation ofthe airways and resultant obstruction of air flow to the lungs in asthmaoften is reversible. In contrast, chronic obstructive pulmonary disease(COPD), also known as chronic obstructive lung disease (COLD), whichalso results in obstruction of air flow to the lungs, is unlike asthmabecause the obstruction often is not reversible, i.e., it is permanent,and often progressive. COPD includes primarily chronic bronchitis andemphysema.

The term, “inflammatory bowel disease” (also known as Irritable BowelSyndrome or IBS) often refers to two chronic diseases that causeinflammation of the intestines: ulcerative colitis and Crohn's disease.In ulcerative colitis (an inflammatory disease of the large intestine,i.e., the colon), the inner lining—or mucosa—of the intestine isinflamed (i.e., the lining of the intestinal wall reddens and swells)and develops ulcers. Ulcerative colitis often is most severe in therectal area. In contrast, Crohn's disease (an inflammatory disease ofthe small intestine) usually involves the lower part of the smallintestine, called the ileum, but it can affect any part of the digestivetract, from the mouth to the anus. In Crohn's disease, the inflammationextends deep into the lining of the affected organ, which can cause painand make the intestines empty frequently, resulting in diarrhea.

Inflammation also has been shown to play a role in cardiovasculardiseases, disorders and conditions. Inflammation of the heart(myocarditis) may result in symptoms such as shortness of breath orfluid retention. In atherosclerosis, the process in which fatty depositsbuild up in the lining of arteries that can contribute to heart attackand stroke, it is believed that the inner layer of arteries becomeinjured by high blood pressure, tobacco smoke, diabetes, or high levelsof triglycerides and cholesterol, thereby triggering an inflammatoryresponse. The inflamed artery lining traps fats, cholesterol, bloodplatelets, calcium and cellular waste, resulting in the production ofplaque. An accumulation of plaque can restrict blood flow through theartery, and rupturing plaque can cause blood clots that block blood flowthrough the artery. Such blood clots also can break loose, travel to theheart and cause a heart attack, or travel to the brain and cause astroke. C-reactive protein (CRP) is one of the acute phase proteins thatincrease during inflammation. It has been suggested that testing the CRPlevel in blood of an individual may be used to assess cardiovasculardisease risk.

In the urinary system, inflammation of the kidneys (nephritis) has beenassociated with high blood pressure and kidney failure. Nephritis hasbeen linked to various diseases, disorders and conditions such as kidneydisease, kidney stones, kidney cancer, gout, Sjogren's Syndrome (anautoimmune disease damaging the eye tear ducts and other glands), lupus,yellow fever and typhoid fever.

Inflammation also has been implicated in various cancers. A genetic linkbetween cancer and inflammation has been discovered by Greten F. R. etal. (Cell, 2004 Aug. 6; 118(3): 285-96), who discovered that theproinflammatory gene I-kappa-B kinase (IKK beta) acts differently in twocell types to initiate cancer, and that deletion of that gene in micedecreased both the incidence of cancer and tumor growth. Strong supportfor a link between inflammation and cancer, including prostate cancer,breast cancer, ovarian cancer, cervical cancer, colon cancer andpancreatic cancer, can be found in, e.g., Bower, V., J. Natl. CancerInstit. Feb. 16, 2005; 97(4): 251-253; Caruso, C. et al., Ann. N.Y.Acad. Sci. December 2004; 1028: 1-13; Macarther, M. et al., Am. J.Physiol. Gastrointest. Liver Phiysiol. April 2004; 286: G515-20;Modugno, F. et al., Cancer Epidemiol Biomarkers Prev. December 2005;14(12): 284047; Moss, S. F. et al., Nat. Clin. Pract. Oncol. February2005; 2(2): 90-97; Neslon, W. G. et al., J Urol. November 2004; 172(5Pt. 2): S6-11; S11-12; Wang, W. et al., Clin. Cancer Res. May 1, 2005;11 (9): 3250-56; Wang, X. et al., J. Translational Med. Jun. 21, 2005;3(25): 1-20; Whitcomb, J. Am. J. Physiol. Gastrointest. Liver Physiol.Aug. 2004; 287: G315-19; and Xu, J. et al., Cancer Epidemiol. BiomarkersPrev. November 2005; 14(11 Pt 1): 2563-68.

Inflammation often is characterized by a strong infiltration ofpolymorphonuclear leukocytes at the site of inflammation, particularlyneutrophils. These cells promote tissue damage by releasing toxicsubstances at the vascular wall or in uninjured tissue. Neutrophilinfiltration results from amplifying cascades of cell-cell communicationinvolving signal transduction proteins, such as G-proteins, that canfacilitate intracellular regulation and intercellular communication byinteracting with a wide range of different regulatoryreceptor-transducer proteins, such as membrane bound receptors. Forthese interactions to occur many of the signal transduction proteins,including virtually all G-proteins, first must be modified by thepost-translational addition of a C₁₅ farnesyl or a C₂₀ geranylgeranylpolyisoprenoid moiety in thioether linkage to a cysteine residue locatedat or near the carboxyl terminus within a so-called CAAX box or relatedcysteine-containing sequence. Carboxy-terminal polyisoprenoid cysteinesthat ultimately result from these modifications can be subject tomethylesterification by a specific membrane associatedS-adenosylmethionine-dependent polyisoprenyl-S-cysteinylmethyltransferase. Compounds that can inhibit these enzymatic reactionsor otherwise alter the interactions among polyisoprenylated signaltransduction proteins, such as G-proteins and the protein regulatorytargets with which they interact, or other intracellular signalingproteins, can be used to mitigate leukocyte responses and,theoretically, to treat inflammatory-related conditions. (See e.g.,Volker, et al., Methods Enzymol., 1995, 250: 216-225).

One signal transduction modulator compound is N-acetyl farnesyl-cysteine(“AFC”), also referred to as N-acetyl-5-trans,trans-farnesyl-L-cysteine. AFC has been shown to inhibitmembrane-associated polyisoprenoid methyl transferase and to block someneutrophil, macrophage, and platelet responses in vitro. Laboratoryresults also indicate that AFC effectively reduces dermal inflammationin mice. AFC requires high concentrations for efficacy and is expectedto result in generalized systemic effects and multiple side effectssince it interferes with a central cell regulation mechanism,characteristics which would seem to preclude its use in vivo. However,because such inhibitory compounds have the potential to be highlyefficacious, there is a need in the art for compositions containing suchcompounds that can act as a safe and effective antidote for variousconditions related to inflammation.

Numerous materials have been used to treat chronic or uncontrolledinflammation, all of which suffer from side effects, some of which areserious, if not life-threatening. For example, products used for reliefof inflammation include, without limitation, corticosteroids and NSAIDs(Non-Steroid Anti-Inflammatory Drugs). Corticosteroids, a class ofsteroids, are used clinically to suppress or control inflammation. Thesub-class of corticosteroids known as glucocorticoids areanti-inflammatory by, amongst other mechanisms, preventing phospholipidrelease and decreasing eosinophil action. Representative examples ofcorticosteroids useful in reducing inflammation include, withoutlimitation, betamethasone, budesonide, cortisone, dexamethasone,hydrocortisone, methylprednisolone, prednisolone, predinsone,triamcinolone, corticosteroid preparations containing salicylic acidderivatives, and other corticosteroidal topical products for joint andmuscular pain that also include tolazoline and dimethyl sulfoxide(“DMSO”). Common side effects of corticosteroids include increasedappetite and weight gain, deposits of fat in chest, face, upper back andstomach, water and salt retention leading to swelling and edema, highblood pressure, diabetes, excess sweating, telangiectasia (dilation ofcapillaries), slowed healing of wounds, osteoporosis, cataracts, acne,hirsutism, muscle weakness, atrophy of the skin and mucous membranes, anincreased susceptibility to infection, and stomach ulcers.

As the name suggests, NSAIDs are not steroids, though these compoundshave a similar eicosanoid-depressing action to steroids in achievingtheir anti-inflammatory effect. Representative examples of NSAIDsinclude, without limitation, aspirin, mofebutazone, clofezone,oxyphenbutazone, benzydamine, etofenamate, piroxicam, felbinac,bufexamac, ketoprofen, bendazac, naproxen, ibuprofen, fentiazac,diclofenac, feprazone, niflumic acid, meclofenamic acid, flurbiprofen,tolmetin, suxibuzone, indometacin, and nifenazone. Aspirin or salicyclicacid was the first discovered member of the NSAIDs class. NSAIDs are notall salicylates, but they have similar effects and mechanisms of action.NSAIDS generally block the activity of the cyclooxygenase (COX) genes,with some blocking both the COX-1 and COX-2 genes, while others moreselectively block only one of the two genes. For example, aspirin blocksboth COX genes, while the newer celecoxib (Celebrex®, Pfizer, Inc., NewYork, N.Y.), rofecoxib (Vioxx®, Ceoxx® and Ceeoxx®, Merck & Co.,Whitehouse Station, N.J.), and valdecoxib (Bextra®, Pfizer) actspecifically on the COX-2 gene, and consequently, are often referred toas COX-2 selective inhibitors or coxibs (CycloOXygenase-2 inhiBitors).Other coxibs include, e.g., Etoricoxib (Arcoxia®, Pfizer) andlumiracoxib (Prexige®, Novartis, Basel, Switzerland).

The specificity of coxibs allows these NSAIDs to reduce inflammationwith minimal gastrointestinal side effects, such as dyspepsia, ulcerperforation, and upper gastrointestinal bleeding that are common withNSAIDs that act on both COX genes. Studies, however, have demonstratedan increased risk of cardiovascular events associated with the use ofthe coxibs celecoxib, valdecoxib and parecoxib than with other NSAIDs.(See, e.g., Solomon et al., N Engl J Med 2005; 352: 1071-80; Nussmeieret al., N Engl J Med 2005; 352:1081-91). Side-effects of NSAIDS varybetween drugs, but generally include nausea, vomiting, diarrhea,constipation, decreased appetite, rash, dizziness, headache, drowsinessand photosensitivity. NSAIDs also may cause fluid retention, leading toedema. The most serious side effects of NSAIDs use are kidney failure,liver failure, ulcers and prolonged bleeding after an injury or surgery.NSAIDs can produce shortness of breath in individuals allergic to them.People with asthma are at a higher risk for experiencing seriousallergic reaction to NSAIDs. Individuals with a serious allergy to oneNSAID are likely to experience a similar reaction to a different NSAID.

Thus, there is a need for a non-steroidal anti-inflammatory compoundthat lacks the side effects of corticosteroids and NSAIDS. It now hasbeen found that signal transduction modulator compounds can impedeinflammation. Without being bound by any particular theory, theimpediment of inflammation likely is a result of the ability of signaltransduction modulator compounds to tone down cell to cell signaling.The present invention, therefore, is directed to compositions and usesof signal transduction modulator compounds for treating and preventinginflammation, and for other unmet needs.

SUMMARY OF THE PRESENT INVENTION

The present invention provides a composition for treating or preventinginflammation comprising:

-   -   a. at least one signal transduction modulator compound, such as,        without limitation, N-acetyl farnesyl-cysteine (AFC), or a        pharmaceutically acceptable salt thereof;    -   b. a carrier; and    -   c. optionally, an additional active ingredient.

The present invention further provides a composition for promotinghealthy joints comprising:

-   -   a. at least one signal transduction modulator compound or a        pharmaceutically acceptable salt thereof;    -   b. a carrier; and    -   c. optionally, an additional active ingredient.

In some embodiments, the composition of the present invention isadministered by a route selected from oral, buccal, cutaneous, nasal,parenteral, vaginal and rectal.

In some embodiments, the at least one signal transduction modulatorcompound of the composition of the present invention is selected fromthe group consisting of:

-   -   a. a compound of Formula (I) or a pharmaceutically acceptable        salt of Formula (I):

-   -   -   wherein:            -   R¹ is a C₁-C₃ alkyl;            -   R² is —COX, wherein X is —OH, —OCH₃, —NH₂, —NHR⁴,                —N(R⁴)₂, or a halogen;            -   R³ is a C₁₀-C₂₅ alkyl or a C₁₀-C₂₅ alkene; and            -   R⁴ is a C₁-C₃ alkyl;

    -   b. when R² is —COOH, a pharmaceutically acceptable salt of        Formula (I) selected from the group consisting of an alkali        metal salt, alkaline earth metal salt, ammonium salt, and        substituted ammonium salt;

    -   c. a compound of Formula (II) or a pharmaceutically acceptable        salt of Formula (II):

W—Y-Q-Z  (II)

-   -   -   wherein:            -   W is a farnesyl group, geranylgeranyl group, substituted                farnesyl group or substituted geranylgeranyl group;            -   Y is —S—, —O—, —Se—, —SO—,

-   -   -   -   —SeO—, —SO₂—, or —SeO₂—; and            -   Q is

-   -   -   -   -   wherein:                -   n, n′ and n″=1, 2, 3, 4, 5, or 6;                -   T_(1′)T_(1″), T_(n′), and T_(n″) are each,                    independently, H, F, Br, —NHCOCH₃, —NH₂, a peptide,                    an alkane group, an alkene group, an                    polyethyleneglycol group, a saturated fatty acid, an                    unsaturated fatty acid, a monosaccharide, or a                    disaccharide;

            -   Z is —CN, —CONH₂, —NO₂, —COOH or salts and esters                thereof —PO₃ or salts or esters thereof, or —SO₃ or                salts or esters thereof; provided that when W is                farnesyl, Y is —S—, n is 2, and either T_(2′) or T_(2″)                is —NHCOCH₃, then Z is not —COOH;

    -   d. a compound of Formula (III) or a pharmaceutically acceptable        salt of Formula (III):

W—Y-Z  (III)

-   -   -   wherein W, Y, and Z are as previously defined;

    -   e. a compound of Formula (IV) or a pharmaceutically acceptable        salt of Formula (IV)

-   -   -   wherein:            -   Z is C—R₁₂ or N;            -   X is —O—, —S—, —SO—, —SO₂—, —NH—, or —Se—;            -   R⁷ is a C₁₀-C₂₅ alkyl or a C₁₀-C₂₅ alkene;            -   R⁸ is H, CN, COOR¹³, SO₃R¹³, CONR¹³R¹⁴, or SO₂N(R¹³)₂,                wherein R¹³ and R¹⁴ are each, independently, hydrogen,                alkyl, alkenyl, —COOM or —SO₃ M, wherein M is a cation;                and            -   R⁹, R¹⁰, R¹¹ and R¹² are each, independently, hydrogen,                carboxyl, alkyl, alkenyl, aminoalkyl, nitroalkyl, nitro,                halogen, amino, mono-alkylamino, di-alkylamino,                mercapto, mercaptoalkyl, azido, or thiocyanato;

    -   f. the quaternary ammonium salts or N-oxides of Formula (IV),        wherein Z is N;

    -   g. a compound of Formula (V) or a pharmaceutically acceptable        salt of Formula (V):

-   -   -   wherein:            -   Z is geranyl, farensyl, geranylgeranyl, phytyl or                3,7-dimethyloctyl;            -   R¹⁵ is butane, butene, methylbutene, CF₃, CF₃CF₂,                CF₃CH₂, CHBr₂,

-   -   h. a compound of Formula (VI) or a pharmaceutically acceptable        salt of Formula (VI):

-   -   -   wherein:            -   R¹⁷ and R¹⁸ are each independently H, CH₃, OCH₃, CN, NO₂                or halogen; and            -   R¹⁹ is H or halogen;

    -   i. a compound of Formula (VII) or a pharmaceutically acceptable        salt of Formula (VII):

-   -   -   wherein:            -   R¹⁷, R¹⁸ and R¹⁹ are as previously defined;

    -   j. a compound of Formula (VIII) or a pharmaceutically acceptable        salt of Formula (VIII):

-   -   k. a compound of Formula (IX) or a pharmaceutically acceptable        salt of Formula (IX)

-   -   l. a compound of Formula (X) or a pharmaceutically acceptable        salt of Formula (X):

-   -   m. a compound of Formula (XI) or a pharmaceutically acceptable        salt of Formula (XI):

-   -   -   wherein:            -   X is 3,7-dimethyloctyl, 3,7-dimethylhexadecene, geranyl,                geranylgeranyl or farnesyl; and            -   X′ is propene, 2-methylbutene or triphenylmethane.

In some embodiments, the at least one signal transduction modulatorcompound of the composition of the present invention is selected fromthe group consisting of:

a. N-acetyl-5-farnesylcysteine;

b. 3-farnesylhomocysteine;

c. N-acetyl-S-oxo-farnesylcysteine;

d. 3-farnesylthio-trans-acrylic acid;

e. 3-farnesylthio-cis-acrylic acid;

f. 3-farnesyloxypropionic acid;

g. 3-farnesylthiobutylic acid;

h. 2-farnesylthioacetic acid sulfoxide;

i. 3-farnesylthiopropionamide;

j. 2-methyl-3-farnestylthiopropionic acid;

k. 2-farnesylthio-1-nitroethane;

l. 2-farnesylthio-S-methyl acetothiohydroximate;

m. 3-farnesylthio-2-methylenepropionic methyl ester;

n. S-farnesylcysteine;

o. N-acetylgeranylgeranylcysteine;

p. 3-farnesylthio-2-nitropropane;

q. 3-farnesylthio-2-methylenepropionic acid;

r. N-benzoyl-S-farnesylcysteine;

s. disodium 2-farnesylthioethyl phosphate;

t. 3-farnesylthiopropionitrile N-acetyl-Se-farnesyl-D,L-cysteine;

u. N-acetyl-S-farnesyl-D-cysteine;

v. 3-farnesylselenopropionic acid;

w. N-acetyl-S-geranyl-L-cysteine;

x. 3-farnesylthiononanoic acid,

y. 3-farnesylthiocyclohexanecarboxylic acid;

z. farnesyl-thiosalicyclic acid;

aa. 2-chloro-5-farnesylaminobenzoic acid;

bb. farnesyl thionicoatinic acid;

cc. 5-fluoro-farnesyl-thiosalicyclic acid;

dd. 5-chloro-farnesyl-thiosalicyclic acid;

ee. 4-chloro-farnesyl-thiosalicyclic acid;

ff. S-farnesyl-methylthiosalicylic acid,

gg. N-Fmoc-S-farnesyl-cysteine;

hh. N-Boc-S-farnesyl-cysteine;

ii. N-phthaloyl-5-farnesyl-cysteine; and

a pharmaceutically acceptable salt thereof.

In some embodiments, the at least one signal transduction modulatorcompound of the composition of the present invention is N-acetylfarnesyl-cysteine or N-acetylgeranylgeranylcysteine. In someembodiments, the at least one signal transduction modulator compound isN-acetyl farnesyl-cysteine. In some embodiments, the signal transductionmodulator comprises N-acetyl farnesyl-cysteine andN-acetylgeranylgeranylcysteine.

In some embodiments, the inflammation that the composition of thepresent invention treats is associated with a joint condition, aninflammation of the airways, or an inflammatory bowel disease. In somesuch embodiments, the joint condition comprises an arthritis or a jointinjury. In some such embodiments, the inflammation of the airwayscomprises an asthma or chronic obstructive pulmonary disease. In somesuch embodiments, the asthma is chronic. In some such embodiments, thechronic obstructive pulmonary disease comprises chronic bronchitis andemphysema. In some such embodiments, the chronic obstructive pulmonarydisease comprises chronic bronchitis. In some such embodiments, theinflammatory bowel disease comprises ulcerative colitis and Crohn'sdisease. In some such embodiments, the inflammatory bowel diseasecomprises ulcerative colitis. In some such embodiments, the inflammatorybowel disease comprises Crohn's disease.

In some embodiments, the at least one signal transduction modulatorcompound of the composition of the present invention is contained withina botanical extract. In some embodiments, the at least one signaltransduction modulator compound of the composition of the presentinvention is contained within a microbial extract.

In some embodiments, the additional active ingredient of the compositionof the present invention is selected from a group consisting of aprotective agent, a demulcent, an emollient, an astringent, a steroidalanti-inflammatory agent, a non-steroidal anti-inflammatory agent, anantioxidant, a chemotherapeutic agent, an antihistamine agent and acleansing agent.

In some embodiments, the composition of the present invention comprisesa mixture selected from the group consisting of a solution, an emulsion,a suspension and a powder.

In some embodiments, the signal transduction modulator compound of thecomposition of the present invention comprises from about 0.01% to about50% w/w of the composition. In some embodiments, the signal transductionmodulator compound comprises from about 0.01% to about 5% w/w of thecomposition.

The present invention further provides a method of treating orpreventing inflammation in a mammal in need thereof, the methodcomprising administering to the mammal a pharmaceutically effectiveamount of a composition comprising:

-   -   a. at least one signal transduction modulator compound or a        pharmaceutically acceptable salt thereof;    -   b. a carrier; and    -   c. optionally, an additional active ingredient.

The present invention further provides a method of promoting healthyjoints in a mammal in need thereof, the method comprising administeringto the mammal a pharmaceutically effective amount of a composition fortreating inflammation comprising:

-   -   a. at least one signal transduction modulator compound or a        pharmaceutically acceptable salt thereof;    -   b. a carrier; and    -   c. optionally, an additional active ingredient.

In some embodiments, the inflammation treated by the method of thepresent invention is associated with a joint condition, an inflammationof the airways or an inflammatory bowel disease.

In some such embodiments, the joint condition comprises an arthritis ora joint injury. In some such embodiments, the composition of the methodof the present invention for treating inflammation further comprises apenetration enhancer.

In some embodiments of the method of the present invention, theinflammation of the airways comprises an asthma or a chronic pulmonaryobstructive disease.

In some embodiments of the method of the present invention, theinflammation is associated with an inflammatory bowel disease.

In some embodiments of the method of the present invention thecomposition is administered by a route that is oral, buccal, parenteral,nasal, vaginal or rectal.

The present invention further provides a kit comprising a compositionfor treating or preventing inflammation, or for promoting healthyjoints, the kit comprises:

-   -   (1) a composition comprising:        -   (a) at least one signal transduction modulator compound or a            pharmaceutically acceptable salt thereof;        -   (b) a carrier, and        -   (c) optionally, an additional active ingredient; and    -   (2) a needle.

In some embodiments, the kit of the present inventions further comprisesa plurality of individual dosage units of the composition and aplurality of needles. In some embodiments, the plurality of individualdosage units and the plurality of needles of the kit of the presentinvention provides for an administration regimen selected from the groupconsisting of daily, weekly and monthly.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1. Induction of edema by TPA.

FIG. 2. AFC, alone, does not cause mouse ear edema.

FIG. 3. AFC inhibits TPA-induced edema.

FIG. 4. AFC treatment produces a dose dependent inhibition ofTPA-induced MPO.

FIG. 5. Histology of AFC inhibition of neutrophil infiltration.

FIG. 6. AFC inhibits TPA-induced neutrophil infiltration.

FIG. 7. AFC inhibition of TPA-induced MPO activity at differentapplication times.

FIG. 8A. AFC does not effect TPA-induced MPO activity in thecontralateral vehicle treated ear.

FIG. 8B. Dexamethasone acts to increase inhibition of TPA-induced MPOactivity in the contralateral vehicle treated ear.

FIG. 8C. Indomethacin acts to increase inhibition of TPA-induced MPOactivity in the contralateral vehicle treated ear.

FIG. 9. AFC inhibits AA-induced induced MPO.

FIG. 10. AFC reduces TPA-induced erythema.

FIG. 11. Inhibition of contact dermatitis in a volunteer.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

In one aspect, the present invention provides compositions having asignal transduction modulator compound, for example and withoutlimitation, N-acetyl farnesyl-cysteine (AFC), for treating, orpreventing, inflammation, or for promoting overall health of the variousanatomical systems and their related joints, tissues, and organs. Thecompositions of the present invention can be employed usefully inpharmaceutical compositions.

In some embodiments, the composition of the present invention is used totreat inflammation. As used herein, “treating,” “treat” or “treatment”includes abrogating, substantially inhibiting, slowing or reversing theprogression of a condition, substantially ameliorating clinical oraesthetical symptoms of a condition, protecting from harmful or annoyingstimuli, or generally promoting health.

In some embodiments, the composition of the present invention is used toprevent inflammation. “Preventing,” “prevent” or “prevention,” as usedherein, includes keeping from happening, anticipating or countering inadvance a condition or symptoms of a condition, including the appearanceof clinical or aesthetical symptoms of a condition, protecting fromharmful or annoying stimuli, or generally promoting health.

In some embodiments, the composition of the present invention is used topromote healthy joints. As used herein, “promoting,” “promote” or“promotion” includes contributing to, furthering, helping or maintainingthe progression and/or growth of a joint.

As used herein the term “inflammation” refers to a physiologic responseto infection and injury in which cells involved in detoxification andrepair are mobilized to the compromised site by inflammatory mediators.The classic signs of inflammation are pain (dolor), heat (calor),redness (rubor), swelling (tumor), and loss of function (functio laesa).Histologically, inflammation involves a complex series of events,including dilatation of arterioles, capillaries and venules, withincreased permeability and blood flow; exudation of fluids, includingplasma proteins; and leukocytic migration into the inflammatory focus.

The term “acute inflammation,” as used herein, refers to inflammation,usually of sudden onset, characterization by the classical signs, withpredominance of the vascular and exudative processes. The term “chronicinflammation,” as used herein, refers to inflammation of slow progressand marked chiefly by the formation of new connective tissue; it may bea continuation of an acute form or a prolonged low-grade form, andusually causes permanent tissue damage.

Regardless of the initiating agent, the physiological changesaccompanying acute inflammation encompass four main features: (1)vasodilation, which results in a net increase in blood flow, is one ofthe earliest physical responses to acute tissue injury; (2) in responseto inflammatory stimuli, endothelial cells lining the venules contract,widening the intracellular junctions to produce gaps, leading toincreased vascular permeability, which permits leakage of plasmaproteins and blood cells out of blood vessels; (3) a strong infiltrationof leukocytes at the site of inflammation, particularly neutrophils,which promote tissue damage by releasing toxic substances at thevascular wall or in uninjured tissue; and (4) fever, produced bypyrogens released from leukocytes in response to specific stimuli.

During the inflammatory process, soluble inflammatory mediators of theinflammatory response work together with cellular components in asystemic fashion in the attempt to contain and eliminate the agentscausing physical distress. The term “inflammatory mediators,” as usedherein, refers to the molecular mediators of the inflammatory process.These soluble, diffusible molecules act both locally at the site oftissue damage and infection and at more distant sites. Some inflammatorymediators are activated by the inflammatory process, while others aresynthesized and/or released from cellular sources in response to acuteinflammation or by other soluble inflammatory mediators. Examples ofinflammatory mediators of the inflammatory response include, but are notlimited to, plasma proteases, complement, kinins, clotting andfibrinolytic proteins, lipid mediators, prostaglandins, leukotrienes,platelet-activating factor (PAF), peptides and amines, including, butnot limited to, histamine, serotonin, and neuropeptides, proinflammatorycytokines, including, but not limited to, interleukin-1, interleukin-4,interleukin-6, interleukin-8, tumor necrosis factor (TNF),interferon-gamma, and interleukin-12.

Inflammation can result from a wide variety of diseases, conditions,syndromes, disorders, injuries and the like of the various anatomicalsystems, including, and without limitation, those of the (1) skeletalsystem including, but not limited to, such diseases, conditions,syndromes, disorders, and injuries, such as (a) arthritis, including,but not limited to, psoriatic arthritis, osteoarthritis, rheumatoidarthritis, juvenile rheumatoid arthritis, juvenile psoriatic arthritis,and Gouty arthritis, (b) soft tissue rheumatic diseases, which arerheumatic diseases that affect the tissues and structures that surrounda joint and produce pain, swelling or inflammation, such as tendonitis,bursitis, and myofascial syndrome, (c) Reiter's syndrome, a triad ofdisorders that can appear consecutively or concurrently that includeinflammation of the urethra, the iris and ciliary body, and the joints(d) Paget's disease, a metabolic bone disease that involves bonedestruction and regrowth which results in deformity, (e) Still'sdisease, in adults, an illness with fever, rash, and joint pain, whichcan lead to chronic arthritis; it is more common in children, where itis called systemic juvenile rheumatoid arthritis, (f) sarcoidosis, animmune system disorder characterized by non-necrotizing granulomas(small inflammatory nodules) that can affect any organ, though the lungsand lymph nodes appear most often affected, (g) Marfan syndrome, aconnective tissue multisystemic disorder characterized by skeletalchanges (arachnodactyl), long limbs, joint laxity, pectus),cardiovascular defects (aortic aneurysm which may dissect, mitral valveprolapse), and ectopia lentis (h) Lyme disease, an inflammatory disordercaused by infection with Borrelia burgdorferi, a nonpyogenic spirochete,(i) lupus, any of several forms of ulcerative skin diseases, including,e.g., systemic lupus erythematosus (SLE) and juvenile SLE, (j) gout. (k)polymyalgia rheumatica, a syndrome within the group of collagen diseasesinvolving pain and stiffness in the hip or shoulder area, (l)fibromyalgia, (m) Ehlers-Danlos syndrome, a group of inherited disordersof the connective tissue, occurring in at least ten types, I to X, basedon clinical, genetic, and biochemical evidence, varying in severity frommild to lethal, and often characterized by hyperelasticity and fragilityof the skin, hypermobility of the joints, and fragility of the cutaneousblood vessels, (n) dermatomyositis, a connective-tissue disease that ischaracterized by inflammation of the muscles and the skin, (O)polymyositis, a chronic, progressive inflammatory disease of skeletalmuscle, (p) scleroderma, a chronic hardening and thickening of the skin,a finding in various different diseases, occurring in a localized orfocal form as well as a systemic disease, (q) spondyloartropathy, any ofseveral diseases affecting the joints of the spine such as ankylosingspondylitis, (r) Behçet's disease, a chronic condition that causescanker sores or ulcers in the mouth and on the genitals, andinflammation in parts of the eye, (s) avascular necrosis, a diseaseresulting from the temporary or permanent loss of the blood supply tothe bones, (t) psoriasis, (u) skin cancer, and (v) bone cancer, (2) therespiratory system, including, but not limited to, such diseases,conditions, syndromes, disorders, and injuries such as (a) asthma,including, without limitation, chronic, atopic, allergic, baker's,bronchial, bronchitic, cardiac, cat, colophony, cough variant,exercise-induced, intrinsic, miller's, nasal, and occupational asthma(b) chronic obstructive pulmonary disease, including, e.g., chronicbronchitis and emphysema, (c) pneumonia, (d) tuberculosis, and (e) lungcancer; (3) the digestive system, including, but not limited to, suchdiseases, conditions, syndromes, disorders, and injuries such as (a)inflammatory bowel disease including Crohn's disease and ulcerativecolitis, (b) eosinophilic disorder, a condition where high numbers ofeosinophils cause inflammation of the digestive tract, (c) gastritis,inflammation and irritation of the stomach, (d) hepatitis, inflammationand irritation of the liver, (e) cholecystitis, inflammation andirritation of the gallbladder, (g) pancreatitis, inflammation andirritation of the pancreas, (h) periodontal disease, (i) gastric cancer,(j) liver cancer, (k) colorectal cancer, and (l) pancreatic cancer; (4)the cardiovascular system, including, but not limited to, such diseases,conditions, syndromes, disorders, and injuries such as (a)atherosclerosis, (b) coronary heart disease, and (c) ischemia; (5) thecerebrovascular system, including, but not limited to, such diseases,conditions, syndromes, disorders, and injuries such as (a) stroke; (6)the nervous system, including, but not limited to, such diseases,conditions, syndromes, disorders, and injuries such as (a) Alzheimer'sdisease, (b) vascular dementia, (c) Parkinson's disease, (d)Huntington's disease, (e) amyotrophic lateral sclerosis, (f) multiplesclerosis, and (g) traumatic brain injury; and (7) the reproductivesystem, including, but not limited to, such diseases, conditions,syndromes, disorders, and injuries such as (a) endometrial cancer, (b)prostate cancer, (c) cervical cancer, (d) ovarian cancer, (e) breastcancer, (f) breast inflammation, (g) endometriosis, (h) prostatitis,inflammation of the prostate gland, (i) penile inflammation, (j)epididymitis, inflammation of the epididymis (a duct of the spermcanal), (k) bartholinitis, an inflammation of Bartholin's duct, (l)vaginitis, (m) salpingitis, inflammation of the oviduct (Fallopiantubes), (n) cervicitis, inflammation of the cervix, (O) oophoritis,inflammation of the ovary, and (p) pelvic inflammatory disease (PID), aninfection of the female reproductive system, of which vaginitis,cervicitis, salpingitis, and oophoritis are subsets.

As used herein, “joint” is meant to include the more or less movablejunction in the body where two or more bones meet and the differentkinds of ligaments, tendons, cartilages, bursae, synovial membranes andbones comprising the mobile skeletal-system of a mammal in variousquantities and configurations. The composition of the present inventionis useful with joints including, but not limited to, ankles, hips,shoulders, knees, wrists, fingers, toes and the like.

As used herein, the terms “signal transduction modulator compound,”“signal transduction modulator” and “STM” refer to a compound that caninhibit, alter or reduce the activity of a G-protein and of the proteinregulatory targets of the G-protein. As used herein a “G-protein” refersto a heterotrimeric polyisoprenylated protein that associates withreceptors of the seven transmembrane domain super family (i.e., Gprotein-coupled receptors (GPCRs)), and is involved in signaltransduction, and to a small GTP-binding signal transduction proteinthat acts to regulate cellular processes, including, but not limited to,cytoskeletal organization and secretion, and to any other protein thatis subject to polyisoprenylation such as, but not limited to, arrestinand nuclear laminar proteins.

Without being limited by theory, compounds known in the art to inhibit,alter or reduce G-protein signal transducing activity act by, interalia, affecting the ability of a G-protein to bind to an interactingregulatory target protein that is frequently, although not always,located in the cell membrane. In order to interact with these regulatorytarget proteins, G-proteins and other polyisoprenylated proteins undergoseveral post-translational modifications including covalent attachmentof a farnesyl or geranylgeranyl moiety in thioether linkage to cysteineresidues located at or in close proximity to their carboxy terminalfarnesyl- or geranylgeranyl-S-cysteine residues.

Inflammatory agonists stimulate the methyl esterification ofpolyisoprenyl-S-cysteinyl residues of some G-proteins (Volker, et al.,Methods Enzymol., 1995, 250: 216-225). Agents that inhibit the methylesterification reaction inhibit G-protein-mediation inflammatoryresponses. Consequently, without being bound by theory, suchpolyisoprenyl-5-cysteine carboxyl methyltransferase inhibitors may serveas anti-inflammatory agents (Volker, et al., Methods Enzymol., 1995,250: 216-225).

Other mechanisms for G-protein inhibition are discussed in Volker, etal. (1991), “effects of farnseylcysteine analogs on protein carboxylmethylation and signal transduction” J. Biol. Chem. 266: 21515-22,herein incorporated by reference.

Non-limiting examples of signal transduction modulator compounds includethose described in U.S. Pat. No. 5,043,268, U.S. Pat. No. 5,202,456,U.S. Pat. No. 5,521,215, U.S. Pat. No. 5,284,867, U.S. Pat. No.5,705,528, U.S. Pat. No. 6,096,740, U.S. Pat. No. 6,372,793, U.S. Pat.No. 6,462,086, U.S. Pat. No. 6,946,485, and Halaschek-Wiener, et al., J.Invest. Dermatol. 2003 January; 120(1): 109-115, each of which isincorporated by reference herein. Other signal transduction modulatorcompounds include cannabinoids such as Δ-tetrahydrodcannabinol (“THC”)and cannabidiol and certain unsaturated fatty acids, such as linoleicacids and omega-3 fatty acids. Additional signal transduction modulatorscan be found in Volker, C. R. 1995. Carboxyl Methiylation at C-terminalS-prenylcsteine residues. Ph.D. thesis, Princeton University, Princeton,N.J. It should be understood that analogs of these compounds that showinhibitor activity also can be useful in the compositions and methods ofthe present invention, as are compounds having different structuralcharacteristics than those described.

In some embodiments, the composition of the present invention has:

-   -   a) at least one signal transduction modulator compound or a        pharmaceutically acceptable salt thereof;    -   b) a carrier, and    -   c) optionally, an additional active ingredient.

In some embodiments, the composition of the present invention can beadministered either orally, cutaneously, nasally, parenterally,vaginally, rectally, or bucally.

As used herein, “oral” or “orally” refers to introduction into the bodyby mouth whereby absorption occurs in one or more of the following areasof the body: the mouth, stomach, small intestine, lungs (alsospecifically referred to as, inhalation), and the small blood vesselsunder the tongue (also specifically referred to as, sublingually).“Nasal” or “nasally,” as used herein, refers to introduction into thebody through the nose whereby absorption occurs through the thin mucousmembrane that lines the nasal passages. In some embodiments, thecomposition of the present invention is in the form of a dispersible drypowder for delivery by inhalation or insufflation (either orally ornasally). Dry powder compositions may be prepared by processes known inthe art, such as lyophilization and jet milling, as disclosed inInternational Patent Publication No. WO 91/16038 and U.S. Pat. No.6,921,527, the disclosures of which are incorporated by reference. Insome embodiments, the composition of the present invention for nasal ororal inhalation or insufflation administration is placed within asuitable dosage receptacle in an amount sufficient to provide a subjectwith a unit dosage treatment. The dosage receptacle is one that fitswithin a suitable inhalation device to allow for the aerosolization ofthe dry powder composition by dispersion into a gas stream to form anaerosol, and then capturing the aerosol produced in a chamber having amouthpiece attached for subsequent inhalation by a subject in need oftreatment. Such a dosage receptacle includes any container enclosing thecomposition known in the art such as gelatin or plastic capsules with aremovable portion that allows a stream of gas (e.g., air) to be directedinto the container to disperse the dry powder composition. Suchcontainers are exemplified by those shown in U.S. Pat. Nos. 4,227,522;U.S. Pat. No. 4,192,309; and U.S. Pat. No. 4,105,027. Suitablecontainers also include those used in conjunction with GlaxoSmithKline'sVentolin® Rotohaler brand powder inhaler (Research Triangle Park, N.C.,USA) or sanofi-aventis's Spinhaler® brand powder inhaler (Holmes Chapel,UK, formerly, Fisons Plc., Loughborough, UK). Another suitable unit-dosecontainer which provides a superior moisture barrier is formed from analuminum foil plastic laminate. The pharmaceutical-based powder isfilled by weight or by volume into the depression in the formable foiland hermetically sealed with a covering foil-plastic laminate. Such acontainer for use with a powder inhalation device is described in U.S.Pat. No. 4,778,054 and is used with GlaxoSmithKline's diskhaler, e.g.,Ventolin Disks® (U.S. Pat. Nos. 4,627,432; 4,811,731; and 5,035,237).

As used herein, “cutaneous” or “cutaneously” refers to application tothe skin for a local (topical) effect or bodywide (systemic) effect suchas that achieved percutaneously (transdermally). Cutaneousadministration involves “topical administration” or “topicallyapplying,” which describes the direct application onto one or moresurfaces including epithelial surfaces covering an affected area, e.g.,a joint. Such a composition can be applied by, e.g., pouring, dropping,spraying, or wiping or rubbing on if a liquid; rubbing or wiping on, ifan ointment, lotion, cream, paste, gel, or the like; dusting, if apowder; spraying, if an aerosol composition; or by any other appropriatemeans. When the composition is sprayed it can be from a compressed airsource or pump. Cutaneous administration also can involve the use oftransdermal administration such as transdermal patches or iontophoresisdevices, which are prepared according to techniques and procedures wellknown in the art. The terms “transdermal delivery system”, transdermalpatch” or “patch” refer to an adhesive system placed on the skin todeliver a time-released dose of a drug(s) by passage from the dosageform through the skin to be available for distribution via the systemiccirculation. Transdermal patches are a well-accepted technology used todeliver a wide variety of pharmaceuticals, including, but not limitedto, scopolaminee for motion sickness, nitroglycerin for treatment ofangina pectoris, clonidine for hypertension, estradiol forpost-menopausal indications, and nicotine for smoking cessation. Patchessuitable for use in the present invention include, but are not limitedto, (1) the matrix patch; (2) the reservoir patch; (3) themulti-laminate drug-in-adhesive patch; (4) the monolithicdrug-in-adhesive patch; and (5) bandage. (See e.g., Transdermal AndTopical Drug Delivery Systems, pp. 249-297 (Tapash K. Ghosh et al. eds.,1997.)) These patches are well known in the art and generally availablecommercially. In some embodiments, the composition of the presentinvention for treating or preventing inflammation or promoting healthyjoints is administered by a route that is cutaneous.

As used herein, “parenteral” or “parenterally” refers to introductioninto the body by way of an injection (i.e., administration byinjection), including, for example, subcutaneously (i.e., an injectionbeneath the skin), intramuscularly (i.e., an injection into a muscle),intravenously (i.e., an injection into a vein), and intrathecally (i.e.,an injection into the space around the spinal cord). A parenterallyadministered composition of the present invention is delivered using aneedle, e.g., a surgical needle. “Surgical needle,” as used herein,refers to any needle adapted for delivery of fluid compositions (i.e.,capable of flow) of the present invention into a selected anatomicalstructure. In some embodiments, the composition of the present inventionfor treating or preventing inflammation or promoting healthy joints isadministered by a route that is parenteral.

“Vaginal” or “vaginally,” as used herein, refers to introduction intothe body through the vagina where absorption occurs through the vaginalwall. In some embodiments, the composition of the present invention fortreating or preventing inflammation or promoting healthy joints isadministered by a route that is vaginal.

“Rectal” or “rectally,” as used herein, refers introduction into thebody through the rectum where absorption occurs through the walls of therectum. The compositions of the present invention for rectaladministration can be in the form of suppositories. These compositionscan be prepared by mixing the drug with a suitable nonirritatingexcipient such as cocoa butter and polyethylene glycols, which are solidat ordinary temperatures but liquid at the rectal temperature, and will,therefore, melt in the rectum and release the drug. When formulated as asuppository the compositions of the invention may be formulated withtraditional binders and carriers, such as triglycerides. In someembodiments, the composition of the present invention for treating orpreventing inflammation or promoting healthy joints is administered by aroute that is rectal.

“Buccal” or “buccally,” as used here in, refers to introduction into thebody by, adjacent to, or toward the cheek such as in the area betweenthe teeth and mucous membranes of the cheek. In some embodiments, thecomposition of the present invention for treating or preventinginflammation or promoting healthy joints is administered by a route thatis buccal.

In some embodiments, the composition of the present invention has atleast one signal transduction modulator compound selected from the groupconsisting of:

-   -   a. a compound of Formula (I) or a pharmaceutically acceptable        salt of Formula (I):

-   -   -   wherein:            -   R¹ is a C₁-C₃ alkyl;            -   R² is —COX wherein X is —OH, —OCH₃, —NH₂, —NHR⁴,                —N(R⁴)₂, or a halogen;            -   R³ is a C₁₀-C₂₅ alkyl or a C₁₀-C₂₅ alkene; and            -   R⁴ is a C₁-C₃ alkyl;

    -   b. when R² is —COOH, a pharmaceutically acceptable salt of        Formula (I) selected from the group consisting of an alkali        metal salt, alkaline earth metal salt, ammonium salt, and        substituted ammonium salt;

    -   c. a compound of Formula (II) or a pharmaceutically acceptable        salt of Formula (II):

W—Y-Q-Z  (II)

-   -   -   wherein:            -   W is a farnesyl group, geranylgeranyl group, substituted                farnesyl group or substituted geranylgeranyl group;            -   Y is —S—, —O—, —Se—, —SO—,

-   -   -   -   —SeO—, —SO₂—, or —SeO₂—; and            -   Q is

-   -   -   -   -   wherein:                -   n, n′ and n″=1, 2, 3, 4, 5, or 6;                -   T_(1′), T_(1″), T_(n′) and T_(n″) are each,                    independently, H, F, Br, —NHCOCH₃, —NH₂, a peptide,                    an alkane group, an alkene group, an                    polyethyleneglycol group, a saturated fatty acid, an                    unsaturated fatty acid, a monosaccharide, or a                    disaccharide;

            -   Z is —CN, —CONH₂, —NO₂, —COOH or salts and esters                thereof, —PO₃ or salts or esters thereof, or —SO₃ or                salts or esters thereof;

        -   provided that when W is farnesyl, Y is —S—, n is 2, and            either T_(2′) or T_(2″) is —NHCOCH₃, then Z is not —COOH;

    -   d. a compound of Formula (III) or a pharmaceutically acceptable        salt of Formula (III):

W—Y-Z  (III)

-   -   -   wherein W, Y, and Z are as previously defined;

    -   e. a compound of Formula (I) or a pharmaceutically acceptable        salt of Formula (IV):

-   -   -   wherein:            -   Z is C—R₁₂ or N;            -   X is —O—, —S—, —SO—, —SO₂—, —NH—, or —Se—;            -   R⁷ is a C₁₀-C₂₅ alkyl or a C₁₀-C₂₅ alkene;            -   R⁸ is H, CN, COOR¹³, SO₃R¹³, CONR¹³R¹⁴, or SO₂N(R¹³)₂,                wherein R¹³ and R¹⁴ are each, independently, hydrogen,                alkyl, alkenyl, —COOM or —SO₃ M, wherein M is a cation;                and            -   R⁹, R¹⁰, R¹¹ and R¹² are each, independently, hydrogen,                carboxyl, alkyl, alkenyl, aminoalkyl, nitroalkyl, nitro,                halogen, amino, mono-alkylamino, di-alkylamino mercapto,                mercaptoalkyl, azido, or thiocyanato;

    -   f. the quaternary ammonium salts or N-oxides of Formula (IV),        wherein Z is N;

    -   g. a compound of Formula (V) or a pharmaceutically acceptable        salt of Formula (V):

-   -   -   wherein:            -   Z is geranyl, farensyl, geranylgeranyl, phytyl or                3,7-dimethyloctyl;            -   R¹⁵ is butane, butene, methylbutene, CF₃, CF₃CF₂,                CF₃CH₂, CHBr₂,

-   -   h. a compound of Formula (VI) or a pharmaceutically acceptable        salt of Formula (VI)

-   -   -   wherein:            -   R¹⁷ and R¹⁸ are each independently H, CH₃, OCH₃, CN, NO₂                or halogen; and            -   R¹⁹ is H or halogen;

    -   i. a compound of Formula (VII) or a pharmaceutically acceptable        salt of Formula (VII):

-   -   -   wherein:            -   R¹⁷, R¹⁸ and R¹⁹ are as previously defined;

    -   j. a compound of Formula (VIII) or a pharmaceutically acceptable        salt of Formula (VIII):

-   -   k. a compound of Formula (IX) or a pharmaceutically acceptable        salt of Formula (IX):

-   -   l. a compound of Formula (X) or a pharmaceutically acceptable        salt of Formula (X):

-   -   m. a compound of Formula (XI) or a pharmaceutically acceptable        salt of Formula (XI):

-   -   -   wherein:            -   X is 3,7-dimethyloctyl, 3,7-dimethylhexadecene, geranyl,                geranylgeranyl or farnesyl; and            -   X′ is propene, 2-methylbutene or triphenylmethane.

In some embodiments of the composition of the present invention, thesignal transduction modulator is a compound of Formula (I) orpharmaceutically acceptable salt thereof, as described above. In someembodiments, the signal transduction modulator of the composition of thepresent invention is a pharmaceutically acceptable salt of Formula (I),as described above, when R² is —COOH selected from the group consistingof an alkali metal salt, alkaline earth metal salt, ammonium salt, andsubstituted ammonium salt. In some embodiments of the composition of thepresent invention, the signal transduction modulator is a compound ofFormula (II) or a pharmaceutically acceptable salt thereof, as describedabove. In some embodiments, the signal transduction modulator s acompound of Formula (III) or a pharmaceutically acceptable salt thereof,as described above. In some embodiments, the signal transductionmodulator of the composition of the present invention is a compound ofFormula (IV) or a pharmaceutically acceptable salt thereof, as describedabove. In some embodiments, the signal transduction modulator is thequaternary ammonium salt or N-oxide of Formula (IV), as described above,wherein Z is N.

In some embodiments of the composition of the present invention, thesignal transduction modulator is a compound of Formula (V) or apharmaceutically acceptable salt thereof, as described above.

In some embodiments of the composition of the present invention, thesignal transduction modulator is a compound of Formula (VI) or (VII) ora pharmaceutically acceptable salt thereof, as described above. In somesuch embodiments, the halogen of R¹⁷, R¹⁸ and R¹⁹ is independentlychorine, fluorine, bromine or iodine. In some such embodiments, R¹⁷, R¹⁸and R¹⁹ are hydrogen. In some such embodiments, R¹⁷ is chlorine and R¹⁸and R¹⁹ are hydrogen. In some such embodiments, R¹⁷ and R¹⁸ are chlorineand R⁹ is hydrogen. In some such embodiments, R¹⁷, R¹⁸ and R¹⁹ arechlorine. In some such embodiments, R¹⁷ is methyl and R¹⁸ and R¹⁹ arehydrogen. In some such embodiments, R¹⁷ and R¹⁸ are methyl and R¹⁹ ishydrogen. In some such embodiments, R¹⁷ and R¹⁹ are hydrogen and R¹⁸ ismethyl. In some such embodiments, R¹⁷ and R¹⁸ are methyl and R¹⁹ ishydrogen. In some such embodiments, R¹⁷ is methoxy and R¹⁸R¹⁹ arehydrogen. In some such embodiments, R¹⁷ and R¹⁹ are hydrogen and R¹⁸ ismethoxy. In some such embodiments, R¹⁷ and R¹⁹ are hydrogen and R¹⁸ iscyano. In some such embodiments, R¹⁷ is cyano and R¹⁸ and R¹⁹ arehydrogen. In some such embodiments, R¹⁷ is fluorine and R¹⁸ and R¹⁹ arehydrogen. In some such embodiments, R¹⁷ and R¹⁹ are hydrogen and R¹⁸ isfluorine. In some such embodiments, R¹⁷ and R¹⁹ are hydrogen and R¹⁸ isnitro. In some such embodiments, R¹⁷ is nitro and R¹⁸ and R¹⁹ arehydrogen. In some such embodiments, R¹⁷ and R¹⁹ are hydrogen and R¹⁸ isbromine.

“Alkyl,” as used herein, denotes a straight (unbranched) or branchedunivalent aliphatic group of 1 to 25 carbon atoms including, e.g.,methyl, ethyl, propyl, isopropyl, decyl, undecyl, dodecyl, octadecyl,nonadecyl, eicosyl, heneicosyl decosyl, tricosyl, tetracosyl, andpentacosyl, and the branched (non-straight-chained) isomers thereof. Insome embodiments of the present invention, the signal transductionmodulator has an alkyl of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25 carbon atoms.

“Alkenyl,” as used herein, denotes a monovalent, straight (unbranched)or branched hydrocarbon chain having one or more double bonds thereinwhere the double bond can be unconjugated or conjugated to anotherunsaturated group (e.g., a polyunsaturated alkenyl) and can beunsubstituted or substituted with one or two suitable substituents. Forexample, and without limitation, the alkenyl can be vinyl, allyl,butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl2-ethylhexenyl, 2-propyl-2-butenyl, 4-(2-methyl-3-butene)-pentenyl,decenyl, undecenyl, dodecenyl, heptadecenyl, octadecenyl, nonadecenyl,eicosenyl, heneicosenyl, docosenyl, tricosenyl, tetracisenyl,pentacosenyl, the branched chain isomers thereof and polyunsaturatedalkenes including octadec-9,12,-dienyl, octadec-9,12,15-trienyl, andeicos-5,8,11,14-tetraenyl.

As used herein, “halogen” refers to the Group VII elements of theperiodic table, including fluorine (F), chlorine (Cl), bromine (Br),iodine (I), and astatine (At).

When the signal transduction modulator is a compound of Formula (I), itis understood that C₁ . . . C_(n) represents 1 to 6 carbon atoms andthat when there are two or more carbon atoms, they are connected in alinear chain by covalent bonds. The covalent bonds may be single,double, or triple bonds. When there are three or more carbon atoms thebonds do not all have to be of the same type. For example, C₁ may beattached to C₂ by a single bond, C₂ may be attached to C₃ by a doublebond. When double or triple bonds are present, two or more of T_(1′) . .. T_(n″) and T_(1″) . . . T_(n″) are eliminated. Each of T_(1′) . . .T_(n′) and T_(1″) . . . T_(n″) is independently: H, F, Br, —NHCOCH₃,—NHCOCH₃, —NH₂, a peptide (such as linked to C_(n) by an amide bond;e.g., of 20 or fewer carbon atoms), or an alkane group (e.g., C₁-C₂₅alkane), an alkene group (e.g., C₂-C₂₅ alkane), an polyethyleneglycolgroup, a saturated fatty acid, an unsaturated fatty acid (such as linkedto C_(n) through an amide bond; e.g., of 20 or fewer carbon atoms), amonosaccharide (such as attached to C_(n) through carbon or oxygen), ora disaccharide (such as attached to C_(n) through carbon or oxygen); andZ is —COOH, salts or esters thereof (e.g., methyl, ethyl, or propylesters). Esters of —COOH, —PO₃, or —SO₃ are preferred to the free acidbecause they are more readily taken up by cells. Many cells haveesterases that can regenerate the free acid, which is in some casespreferred for inhibition of methylation. An unsaturated fatty acid, amonosaccharide, or a disaccharide.

Regarding the farnesyl, farnesyl cysteine, geranylgeranyl andgeranylgeranyl cysteine moieties, a hydrogen atom generally can bereplaced by a fluorine atom, and a methyl group generally can bereplaced by a bromine atom. Accordingly, “substituted farnesyl group”means a farnesyl moiety in which one or more hydrogens have beensubstituted by a fluorine atom or one or more methyl groups have beensubstituted a bromine atom, and “substituted geranylgeranyl group” meansa geranylgeranyl moiety in which one or more hydrogen atoms have beenreplaced by one or more fluorine atoms, or one or more methyl groupshave been substituted by one or more bromine atoms.

In some embodiments, the composition of the present invention has atleast one signal transduction modulator compound selected from the groupconsisting of:

a. N-acetyl-5-farnesylcysteine;

b. 3-farnesylhomocysteine;

c. N-acetyl-S-oxo-farnesylcysteine;

d. 3-farnesylthio-trans-acrylic acid;

e. 3-farnesylthio-cis-acrylic acid;

f. 3-farnesyloxypropionic acid;

g. 3-farnesylthiobutyric acid;

h. 2-farnesylthioacetic acid sulfoxide;

i. 3-farnesylthiopropionamide;

j. 2-methyl-3-farnestylthiopropionic acid;

k. 2-farnesylthio-1-nitroethane;

l. 2-farnesylthio-S-methyl acetothiohydroximate;

m. 3-farnesylthio-2-methylenepropionic methyl ester;

n. S-farnesylcysteine;

o. N-acetylgeranylgeranylcysteine;

p. 3-farnesylthio-2-nitropropane;

q. 3-farnesylthio-2-methylenepropionic acid;

r. N-benzoyl-5-farnesylcysteine;

s. disodium 2-farnesylthioethyl phosphate;

t. 3-farnesylthiopropionitrile N-acetyl-Se-farnesyl-D,L-cysteine;

u. N-acetyl-5-farnesyl-D-cysteine;

v. 3-farnesylselenopropionic acid;

w. N-acetyl-5-geranyl-L-cysteine;

x. 3-farnesylthiononanoic acid;

y. 3-farnesylthiocyclohexanecarboxylic acid;

z. farnesyl-thiosalicyclic acid;

aa. 2-chloro-5-farnesylaminobenzoic acid;

bb. farnesyl thionicoatinic acid;

cc. 5-fluoro-farnesyl-thiosalicyclic acid;

dd. 5-chloro-farnesyl-thiosalicyclic acid;

ee. 4-chloro-farnesyl-thiosalicyclic acid;

ff. S-farnesyl-methylthiosalicylic acid;

gg. N-Fmoc-S-farnesyl-cysteine;

hh. N-Boc-S-farnesyl-cysteine;

ii. N-phthaloyl-5-farnesyl-cysteine; and

a pharmaceutically acceptable salt thereof.

In some embodiments, the composition of the present invention has atleast one signal transduction modulator compound that is N-acetylfarnesyl-cysteine or N-acetylgeranylgeranylcysteine. In someembodiments, the signal transduction modulator compound of thecomposition of the present invention is N-acetyl farnesyl-cysteine. Insome embodiments, the signal transduction modulator compound of thecomposition of the present invention is N-acetyl farnesyl-cysteine andN-acetylgeranylgeranylcysteine.

In some embodiments of the present invention, the composition furtherhas at least one penetration enhancer or propellant. A “penetrationenhancer,” as used herein, is an agent known to accelerate the deliveryof a substance through the skin by, e.g., disrupting the barrierfunction of the skin without compromising its barrier effects onmicroorganisms and toxins. The penetration enhancer used in theinvention should be applicable to skin (e.g., human) and compatible withthe compound. Suitable penetration enhancers for this invention include,for example, and without limitation, such substances as dipolar-aproticsolvents, which include dimethylsulfoxide (“DMSO”), dimethyl formamide(“DMF”), N,N-dimethylacetamide (“DMA”), decylmethylsulfoxide (“C₁₀MSO”),and N-methyl-2-pyrrolidone, the 1-substituted azacycloheptane-2-ones,particularly 1-n-dodecylcyclazacycloheptan-2-one (available under thetrademark Azone® from Whitby Research Incorporated, Richmond, Va.),phospholipids such as lecithin, alcohols including glycerols such aspolyethylene glycol monolaurate (“PGML”), glycerol monolaurate (“GML”),and fatty acid alcohols, allantoin, urazole, and the like. Thepenetration enhancer also can be a vegetable oil, such as, but notlimited to, safflower oil, cottonseed oil, corn oil, olive oil.Additional penetration enhancers generally can be found in Remington:The Science and Practice of Pharmacy, 20^(th) ed. (Gennaro, A. R., etal., eds.) Lippincott Williams & Wilkins: Philadelphia (2000), which isincorporated herein by reference. As used herein, “propellant” refers toan agent that propels the delivery of a composition in, e.g., avaporized, aerosol nebulized, or spray form. Propellants often are usedin metered-dose inhalers for the treatment of asthma and otherrespiratory disorders and for systemic treatments such as insulin fordiabetes. Propellants also are used, for example, in nasal inhalers fortreatment of allergic rhinitis, topical sprays, oral sprays, and otheraerosol applications. An example of such propellants, withoutlimitation, are the Dymel® pharmaceutical propellants manufactured byDuPont™ (Wilnrington, Del.).

In some embodiments, the composition of the present invention includes apharmaceutically acceptable penetration enhancer. The term“pharmaceutically acceptable penetration enhancer,” as used herein,refers to any substantially non-toxic substance that improves thebioavailability of the composition of the present invention.Pharmaceutically acceptable penetration enhancers are usefulconventionally for topical administration of pharmaceuticals in which,e.g., the signal transduction modulator compound remains stable andbioavailable when applied directly to skin.

As used herein, the terms “carrier” and “pharmaceutical carrier” referto a pharmaceutically acceptable inert agent or vehicle for deliveringone or more active agents to a mammal, and often is referred to as“excipient.” The (pharmaceutical) carrier must be of sufficiently highpurity and of sufficiently low toxicity to render it suitable foradministration to the mammal being treated. The (pharmaceutical) carrierfurther should maintain the stability and bioavailability of an activeagent, e.g., a signal transduction modulator compound of the presentinvention. The (pharmaceutical) carrier can be liquid or solid and isselected, with the planned manner of administration in mind, to providefor the desired bulk, consistency, etc., when combined with an activeagent and other components of a given composition. The (pharmaceutical)carrier can be, without limitation, a binding agent (e.g.,pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose, etc.), a filler (e.g., lactose and other sugars,microcrystalline cellulose, pectin, gelatin, calcium sulfate, ethylcellulose, polyacrylates, calcium hydrogen phosphate, etc.), a lubricant(e.g., magnesium stearate, talc, silica, colloidal silicon dioxide,stearic acid, metallic stearates, hydrogenated vegetable oils, cornstarch, polyethylene glycols, sodium benzoate, sodium acetate, etc.), adisintegrant (e.g., starch, sodium starch glycolate, etc.), or a wettingagent (e.g., sodium lauryl sulphate, etc.). Other suitable(pharmaceutical) carriers for the compositions of the present inventioninclude, but are not limited to, water, salt solutions, alcohols,polyethylene glycols, gelatins, amyloses, magnesium stearates, talcs,silicic acids, viscous paraffins, hydroxymethylcelluloses,polyvinylpyrrolidones and the like. Compositions of the presentinvention that are for cutaneous administration of the signaltransduction modulator compound, such as topical (i.e., local), caninclude (pharmaceutical) carriers such as sterile and non-sterileaqueous solutions, non-aqueous solutions in common solvents such asalcohols, or solutions of the signal transduction modulator compound inliquid or solid oil bases. Such (pharmaceutical) carrier solutions alsocan contain buffers, diluents and other suitable additives. Compositionsof the present invention that are for parenteral administration of thesignal transduction modulator compound, such as intramuscular orsubcutaneously, can include (pharmaceutical) carriers such as sterileaqueous solutions, non-aqueous solutions in common solvents such asalcohols, or solutions of the signal transduction modulator compound ina liquid oil base.

In some embodiments, the carrier of the composition of the presentinvention includes a release agent such as sustained release or delayedrelease carrier. In such embodiments, the carrier can be any materialcapable of sustained or delayed release of the signal transductionmodulator compound to provide a more efficient administration, e.g.,resulting in less frequent and/or decreased dosage of the signaltransduction modulator compound, improve ease of handling, and extend ordelay effects on diseases, disorders, conditions, syndromes, and thelike, being treated, prevented or promoted. Non-limiting examples ofsuch carriers include liposomes, microsponges, microspheres, ormicrocapsules of natural and synthetic polymers and the like. Liposomesmay be formed from a variety of phospholipids such as cholesterol,stearylamines or phosphatidylcholines.

As used herein, “moisturizing agent” refers to a substance that adds orrestores moisture to the skin or a mucous membrane. Representativeexamples of moisturizing agents (often referred to as humectants) thatare suitable in the present invention include, but are not limited to,guanidine, glycolic acid and glycolate salts, Aloe vera in any of itsvariety of forms, allantoin, urazole, polyhydroxy alcohols such assorbitol, glycerol, hexanetriol, polypropylene glycol, butylene glycol,hexylene glycol and the like, polyethylene glycols, sugars and starchesand their derivatives, hyaluronic acid, lactamide monoethnolamine,acetamide mono ethanol amine, and any combination thereof.

As used herein, “fragrance,” refers to a substance having a pleasantaroma Suitable fragrances include, without limitation, eucalyptus oil,camphor synthetic, peppermint oil, clove oil, lavender, chamomile, andthe like.

The term “chelating agent,” as used herein, refers to a ligand, atom,ion or functional group that binds to a metal ion such as calcium(Ca²⁺), magnesium (Mg²⁺) and copper (Cu²⁺, forming a metal complex knownas a chelate. In some embodiments of the present invention, thecomposition further optionally contains a chelating agent, e.g., a mildagent, such as, ethylenediaminetetraacetic acid (“EDTA”), EDTAderivatives, or any combination thereof. In some embodiments, thechelating agent enhances the preservative or preservative system of thecomposition. Suitable preservatives for use in the compositions of thepresent invention include, but are not limited to, one or more alkanols,disodium EDTA, EDTA salts, EDTA fatty acid conjugates, isothiszolinone,parabens such as methylparaben and propylparaben, polypropylene glycols,sorbates, urea derivatives such as diazolindinyl urea, or anycombination thereof.

The term “emulsifiers,” as used herein, promote the formation andstabilization of an emulsion. Suitable emulsifiers can be naturalmaterials, finely divided solids, or synthetic materials. Naturalemulsifying agents can be derived from either animal or vegetablesources. Those from animal sources include, e.g., gelatin, egg yolk,casein, wool fat, and cholesterol. Those from vegetable sources include,e.g., acacia, tragacanth, chondrus, and pectin. Vegetable sourcesspecifically from cellulose derivatives include, e.g., methyl celluloseand carboxymethyl cellulose, and often are used to increase viscosity.Finely divided emulsifiers include, e.g., bentonite, magnesiumhydroxide, aluminum hydroxide, and magnesium trisilicate. Syntheticemulsifiers include, e.g., anionic, cationic, or nonionic agents such assodium lauryl sulfate, benzalkonium chloride, polyethylene glycol 400monostearate and any combinations thereof.

The term “thickeners,” as used herein, refers to agents that make acomposition dense or viscous in its consistency. Suitable thickeners forthe compositions of the present invention include, e.g., non-ionicwater-soluble polymers such as hydroxyethylcellulose (commerciallyavailable under the trademark Natrosol® 250 or 350), cationic watersoluble polymers such as Polyquat 37 (commercially available under thetrademark Synthalen®CN), fatty alcohols, fatty acids, anionic polymersand their alkali salts, and mixtures thereof.

As used herein, “solublizing agents” refers to substances that enable asolute to dissolve in a medium in which the solute is otherwiseinsoluble. Representative examples of solublizing agents that aresuitable in the present invention include, without limitation,complex-forming solublizers such as citric acid, EDTA, sodiummeta-phosphatate, succinic acid, urea, cyclodextrin,polyvinylpyrrolidone, diethylammonium-ortho-benzoate, and micelleforming solubilizers such as TWEEN® polysorbates (e.g. TWEEN 80® andTWEEN 60®) and Span sorbitan esters (e.g. sorbitan monostearate (Span60) and sorbitan monoleate (Span 80)). Other solublizers that are usefulin the compositions of the present invention are, for example,polyoxyethylene sorbitan fatty acid esters, polyoxyethylene n-alkylamine n-oxides, polyoxamers, organic solvents such as acetone,phospholipids, and cyclodextrins.

As used herein, “anti-irritant” refers to an agent that prevents orreduces soreness, roughness, or inflammation of a body part. Suitableanti-irritants for use in the present invention include, for example,steroidal and non-steroidal anti-inflammatory agents or other materialssuch as Aloe vera, chamomile, alpha-bisabolol, cola nitida extract,green tea extract, tea tree oil, licoricic acid, allantoin, caffeine orother xanthines, glycyrrhizic acid and its derivatives, and mixturesthereof. Anti-irritants can be divided into water-soluble anti-irritantsand water-insoluble anti-irritants with representative examplesdescribed in, for example U.S. Pat. No. 5,482,710, which is incorporatedherein by reference.

The term “colorant,” as used herein, refers to a substance that gives orchanges color of a composition, and includes pigments or dyes or acombination thereof. Suitable pigments for use in the compositions ofthe present invention include, without limitation, iron oxides andtitanium oxides, while suitable dyes include FD&C approved colorants,D&C approved colorants, and those approved for use in Europe and Japan.See Marmion, D. N., “Handbook of U.S. Colorants for Food, Drugs,Cosmetics, and Medical Devices,” 3^(rd) ed., 1991 (John Wiley & Sons,New York), incorporated herein by reference.

The term “surfactants,” as used herein, refers to surface-activesubstances, such as a detergent. Suitable surfactants for use with thepresent invention include, but are not limited to, sarcosinates,glutamates, sodium alkyl sulfates, ammonium alkyl sulfates, ammoniumalkyleth sulfates, ammonium laureth-n-sulfates, sodiumlaureth-n-sulfates, isothionates, glycerylether sulfonates,sulfosuccinates and combinations thereof. In some embodiments, thecomposition of the present invention includes an anionic surfactantselected from the group consisting of sodium lauroyl sarcosinate,monosodium lauroyl glutamate, sodium alkyl sulfates, ammonium alkylsulfates, sodium alkyleth sulfates, and combinations thereof.

In some embodiments, the composition of the present invention treats orprevents inflammation. In some embodiments, the inflammation isassociated with a joint condition, inflammation of the airways, orinflammatory bowel disease. In some embodiments, the joint conditionincludes arthritis or a joint injury. The joint injury can be a sprain,ligament tear, tendon tear, strained ligament, strained tendon, ligamentrupture, tendon rupture, cartilage tear, or some other joint injury.

In some embodiments, the inflammation of the airways being treated orprevented by a composition of the present invention includes an asthmaor chronic obstructive pulmonary disease. In some embodiments, theasthma is chronic. In some embodiments, the chronic obstructivepulmonary disease includes chronic bronchitis and emphysema; or chronicbronchitis. In some embodiments, the inflammatory bowel disease includesulcerative colitis and Crohn's disease; ulcerative colitis; or Crohn'sdisease.

The term “disease” or “disorder,” as used herein, refers to animpairment of health or a condition of abnormal functioning. The term“syndrome,” as used herein, refers to a pattern of symptoms indicativeof some disease or condition. The term “injury,” as used herein, refersto damage or harm to a structure or function of the body caused by anoutside agent or force, which may be physical or chemical. A “jointinjury,” as used herein, includes a variety of conditions resulting fromsome mechanical damage to a joint due to some outside force beingapplied to the joint, or due to turning, extending, flexing, twisting,or otherwise using the joint in a way that does damage to its componenttissues and/or compromises its ability to function normally. The term“condition,” as used herein, refers to a variety of health states and ismeant to include disorders or diseases, injury, the promotion of healthyjoints, tissue and organs, and inflammation caused by any underlyingmechanism or disorder.

In some embodiments, the composition of the present invention is apharmaceutical composition. A “pharmaceutical composition,” as usedherein, refers to a composition, which has under gone federal regulatoryreview, that prevents, reduces in intensity, cures, ameliorates, orotherwise treats a target disorder or disease.

In some embodiments, the signal transduction modulator compound of thecomposition of the present invention is contained within a botanicalextract. Botanical extracts can be assayed for signal transductionmodulator activity by using the methods described herein. As usedherein, a “botanical extract” refers to a fresh or processed (e.g.,cleaned, frozen, dried, sliced, liquefied) part of a single species ofplant, alga or macroscopic fungus.

In some embodiments, the signal transduction modulator compound of thecomposition of the present invention is contained within a microbialextract. As used herein, “microbial extract” refers to a fresh orprocessed (e.g., cleaned, frozen, dried, liquefied, dissolved, pelleted)part of a microbial culture. The term “microbial,” “microbe” or“microorganism,” as used herein, refers to an organism too small to beseen clearly with the naked eye, including, but not limited to,bacteria, fungi, molds, algae, protozoan and viruses. Microbial extractscan be assayed for signal transduction modulator activity according tothe methods described herein.

In some embodiments, the composition of the present invention has anadditional active ingredient. As used herein, “additional activeingredient” refers to an agent, other than a signal transductionmodulator compound of the present invention, that exerts apharmacological, dermatological or any other beneficial activity. Theadditional active ingredient should be compatible with the signaltransduction modulator compound of the present invention. The term“compatible,” as used herein, means that the active ingredients of acomposition are capable of being combined with each other in a mannersuch that there is no interaction that would substantially reduce theefficacy of each active ingredient or the composition under ordinary useconditions. It is to be understood that “other beneficial activity” canbe one that is perceived only as such by the subject using the inventivecompositions. In some embodiments, the signal transduction modulatorcompound of the inventive composition is a new excipient. As usedherein, a “new excipient” refers to any inactive ingredient that isadded intentionally to the composition of the present invention and isnot intended to exert a therapeutic effect at the intended dosage,although it may act to improve product delivery. A new excipient is notfully qualified by existing safety data with respect to the currentlyproposed level of exposure, duration of exposure, or route ofadministration. Additional characteristics of new excipients can befound in the “Guidance for Industry Nonclinical Studies for the SafetyEvaluation of Pharmaceutical Excipients” issued by the Center for DrugEvaluation and Research, U.S. Food and Drug Administration, in May 2005,herein incorporated by reference.

In some embodiments, the compositions of the present invention furthercan include one or more compatible active ingredients that are aimed atproviding the composition with another pharmaceutical effect, inaddition to that provided by a signal transduction modulator compound ofthe inventive composition.

In some such embodiments, the additional active ingredient is selectedfrom one or more protective agent, demulcent, emollient, astringent,steroidal anti-inflammatory agent, non-steroidal anti-inflammatoryagent, antioxidant, chemotherapeutic agent, antihistamine agent,cleansing agent or combination thereof.

In the broadest pharmacological sense a “protective agent” or“protectives,” as used herein, refers to any agent that isolates theexposed surface of skin or membrane (e.g., mucous membrane) from harmfulor annoying stimuli. A protective can take the form of dusting powders,adsorbents, mechanical protective agents, and plasters. Dusting powdersare relatively inert and insoluble materials that are used to cover andprotect, e.g., epithelial surfaces, ulcers, and wounds. Usually thesesubstances are finely subdivided powders that absorb moisture and canact as a desiccant. The absorption of skin moisture decreases frictionand also discourages certain bacterial growth. Some of the materialsthat are used as protective adsorbents include bentonite, insolublesalts of bismuth, boric acid, calcium carbonate (precipitated),cellulose, corn starch, magnesium stearate, talc, titanium dioxide, zincoxide, and zinc stearate.

A protective also can be administered to the skin to form an adherent,continuous film that can be flexible or semi-rigid depending on thematerials and the formulations as well as the manner in which theyapply. This protective material can serve several purposes includingproviding occlusion from the external environment, providing chemicalsupport, and serving as vehicles for other medicaments. Mechanicalprotectives generally are either collodions or plasters. Examplesinclude, without limitation, aluminum hydroxide gel, collodions,dimethicone, petrolatum gauze, adsorbable gelatin film, adsorbablegelatin sponge, zinc gelatin, kaolin, lanolin, anhydrous lanolin,mineral oil, mineral oil emulsion, mineral oil light, olive oil, peanutoil, petrolatum, silicones, and the like.

Demulcents are protective agents that are employed primarily toalleviate irritation, particularly mucous membranes or abraded tissues.They often are applied to the surface in viscid, sticky preparationsthat cover the area readily and can be medicated. A number of chemicalsubstances possess demulcent properties. These substances include, e.g.,the alginates, mucilages, gums, dextrins, starches, certain sugars, andpolymeric polyhydric glycols. Other demulcents include, e.g., acacia,agar, benzoin, carbomer, gelatin, glycerin, hydroxyethyl cellulose,hydroxypropyl cellulose, hydroxypropyl methylcellulose, propyleneglycol, sodium alginate, tragacanth, and the like.

The term “emollients,” as used herein refers to substances thatgenerally are bland, fatty, or oleaginous materials that can be appliedlocally, particularly to skin. Emollients are moisturizers that increasethe tissue moisture content thereby rendering the skin softer and morepliable. Increased moisture content in the skin can be achieved bypreventing water loss with an occlusive water-immiscible barrier,increasing the water-holding capacity in the skin with humectants oraltering the desquamation of the outermost skin layer, the stratumcorneum. Useful emollients for the present invention include, e.g.,lanolin, spermaceti, mineral oil, paraffin, petrolatum, white ointment,or yellow ointment, and the like; as well as, e.g, vegetable oils,waxes, cetyl alcohol, glycerin, hydrophilic petrolatum, isopropylmyristate, myristyl alcohol, and oleyl alcohol.

The term “astringents,” as used herein, refers to compounds that areapplied locally to tissue (e.g., skin) such as protein precipitants thathave such low cell penetrability that the action is limited essentiallyto the cell surface and interstitial spaces. The astringent action isaccompanied by contraction and wrinkling of the tissue and by blanching.Astringents are used therapeutically to arrest hemorrhage by coagulatingthe blood, promote healing, toughen the skin, or decrease sweating. Theprinciple components of astringents are salts of aluminum, zinc,manganese, iron, or bismuth. Certain other salts may also be used, suchas permanganates and tannins, or related polyphenolic compounds and thelike.

The term “cleansing agents,” as used herein, includes detergents (i.e.,soaps) and non-soap detergents, and the like.

The term “irritant,” as used herein, refers to a material that actslocally on the skin to induce, based on irritant concentration,hyperemia, inflammation, and vesication. The agents that induce onlyhyperemia are also known as rubefacients. A “rubifacient,” as usedherein, refers to a material that produces increased circulation to aninjured area, accompanied by a feeling of comfort, warmth, and sometimesitching and hyperesthesia. Some of these standard irritants are alcohol,aromatic ammonia spirits, benzoin tincture, camphor capsicum, coal tarextracts and the like.

The term “steroidal anti-inflammatory agent,” as used herein, refers toany one of numerous compounds containing a 17-carbon 4-ring systemincluding, e.g., the sterols, various hormones (such as anabolicsteroids), and glycosides. Representative examples of steroidalanti-inflammatory agents include, without limitation, corticosteroidssuch as hydrocortisone, hydrooxyltriamcinolone, alpha-methyldexamethasone, dexamethasone-phosphate, beclomethasone dipropionates,clobetasol valerate, desonide, deoxymethasone, desoxycorticosteroneacetate, dexamethasone, dichlorisone, diflorasone diacetate,diflucortolone valerate, fluadrenolone, fluclorolone acetonide,fludrocortisone, flumethasone pivalate, fluosinolone acetonide,fluocinonide, flucortine butylesters, fluocortolone, fluprednidene(fluprenylidene) acetate, flurandrenolone, halcinonide, hydrocortisoneacetate, hydrocortisone butyrate, methylprednisolone, triamcinoloneacetonide, cortisone, cortodoxone, flucetonide, fludrocortisone,difluorosone diacetate, fluradrenolone, fludrocortisone, difluorosonediacetate, fluradrenolone acetonide, medrysone, amcinafel, amcinafide,betamethasone and the balance of its estes, chloroprednisone,chloroprednisone acetate, clocortelone, clescinolone, dichlorisone,diflurprednate, flucloronide, flunisolide, fluoromethalone, fluperolone,fluprednisolone, hydrocortisone valerate, hydrocortisonecyclopentylpropionate, hydrocortamate, meprednisone, paramethasone,prednisolone, prednisone, beclomethasone dipropionate, triamcinolone,and mixtures thereof.

The term “non-steroidal anti-inflammatory agent” or “NSAID,” as usedherein, refers to a large group of agents, as previously describedherein. Examples of non-steroidal anti-inflammatory agents that aresuitable for the compositions of the present invention include, withoutlimitation, aspirin, ibuprofen, naproxen sodium, oxicams, such aspiroxicam, isoxicam, tenoxicam, sudoxicam, and CP-14,304; disalcid,benorylate, trilisate, safapryn, solprin, diflunisal, and fendosal;acetic acid derivatives, such as diclofenac, fenclofenac, indomethacin,sulindac, tolmetin, isoxepac, furofenac, tiopinac, zidometacin,acemetacin, fentiazac, zomepirac, clindanac, oxepiniac, felbinac, andketorolac; fenamates, such as mefenamic, meclofenamic, flufenamic,niflumic, and tolfenamic acids; propionic acid derivatives, such asibuprofen, naproxen, benoxaprofen, fluribiprofen, ketoprofen,fenoprofen, fenbufen, indopropfen, pirprofen, caipofen, oxaprozin,pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, andtiaprofenic; pyrazoles, such as phenylbutazone, oxyphenbutazone,feprazone, azapropazone, trimethazone. Mixtures of non-steroidalanti-inflammatory agents also can be employed, as well as thepharmaceutically and/or dermatologically-acceptable salts and estersthereof such as etofenamate, a flufenamic acid derivative, which isparticularly useful for topical administration.

The term “antioxidant agent,” as used herein, refers to a substance thatinhibits oxidation or reactions promoted by oxygen or peroxides.Non-limiting examples of antioxidants that are suitable for thecompositions of the present invention include, e.g., ascorbic acid(vitamin C) and its salts, ascorbyl esters of fatty acids, ascorbic acidderivatives (e.g., magnesium ascorbyl phosphate, sodium ascrobylphosphate, and ascorbyl sorbate), tocopherol (vitamin E), tocopherolsorbate, tocopherol acetate, other esters of tocopherol, butylatedhydroxy benzoic acids and their salts,6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (commerciallyavailable under the tradename Trolox®), gallic acid and its alkylesters, especially propyl gallate, uric acid and its salts and alkylesters, sorbic acid and its salts, lipoic acid, amines (e.g.,N,N-diethylhydroxylamine and amino-guanidine), sulfhydryl compounds(e.g., glutathione), dihydroxy fumaric acid and it salts, glycinepidolate, arginine pilolate, nordihydroguaiaretic acid, bioflavinoids,curcumin, lyseine, methionine, proline, superoxide dismutase, silymarin,tea extracts, grape skin and seed extracts, melanin, and rosemaryextracts.

The term “chemotherapeutic agent,” as used herein, refers to a chemicaluseful in the treatment or control of a disease. Non-limiting examplesof chemotherapeutic agents suitable for the present invention includedaunorubicin, doxorubicin, idarubicin, amrubicin, pirarubicin,epirubicin, mitoxantrone, etoposide, teniposide, vinblastine, mitomycinC, fluorouracil (5-FI), paclitaxel, docetaxel, actinomycin D,colchicines, topotecan, irinotecan, geincitabine cyclosporine,verapamil, valspodor, probenecid,(E)-3-[[[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-[[3-dimethylamino)-3-oxopropyl]thio]methyl]thio]-propanoicacid (MK571),N-(4[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolyl)-ethyl]-phenyl-9,10-dihydro-5-methoxy-9-oxo-4-acridinecarboxamide (elacridar, GF129918), zosuquidar trihydrochloride(LY335979), biricodar, terfenadine, quinidine, pervilleine A andtariquidar (XR9576).

The term “antihistamine agent,” as used herein, refers to a compoundthat counteracts histamine in the body and is used for treating allergicreactions and cold symptoms. Non-limiting examples of antihistamineagents suitable for the present invention include chloropheniramine,brompheniramine, dexchloropeniramine, tripolidine, clemastine,diphenhydramine, promethazine, piperazines, piperidines, astemizole,loratadine and terfenadine.

The term “hormone,” as used herein, refers to a natural substanceproduced by organs of the body that travel by blood to trigger activityin other locations or their synthetic analogs. Suitable hormones for thepresent invention include, but are not limited to, calciferol (VitaminD₃) and its products, androgens, estrogens, and progesterones.

The term “caustic agent,” as used herein, refers to substances capableof destroying or eating away epithelial tissue by chemical action.Caustic agents can be used to remove dead skin cells. For example,beta-hydroxy acids, which are naturally derived acids with a strongkerolytic effect, are useful for acne or peeling outer layers of theskin.

In some embodiments, the composition of the present invention includes amixture selected from a solution, emulsion, suspension and powder. Insome such embodiments, the suspension is a gel, aerosol or paste. Asused herein, “suspension” refers to a colloidal mixture in which afinely-divided species is combined with another species, with the formerbeing so finely divided and mixed that it does not rapidly settle out Asuspension of liquid droplets or fine solid particles in a gas is calledan “aerosol.” As used herein, “paste” refers to a suspension thatbehaves as a solid until sufficient stress is applied, at which point itflows like a fluid. As used herein, “gel” refers to a suspension havinga dispersed phase with a dispersion medium or matrix, resulting in aviscous, jelly-like, semisolid material. When water is the dispersionmedium the gel is often referred to as a hydrogel.

In some such embodiments, the composition is a solution. A solution isgenerally considered as a homogeneous mixture of two or more substances;it is frequently, though not necessarily, a liquid. In a solution, themolecules of the solute or dissolved substance are uniformly distributedamong those of the solvent. Solvents that can be useful in thecompositions of the present invention include water, as well as organicsolvents such as the alcohols (e.g. ethanol or isopropanol, acetone).

In some embodiments, the composition of the present invention is anemulsion. As used herein, “emulsion” refers to a colloid system in whichboth the dispersed phase and the dispersion medium are immiscibleliquids where the dispersed liquid is distributed in small globulesthroughout the body of the dispersion medium liquid. The globule size iscritical and must be such that the system achieves maximum stability.Usually, separation of the two phases will occur unless a thirdsubstance, an emulsifying agent, is incorporated. Thus, a stable basicemulsion contains at least the two liquids and the emulsifying agent,and often additionally, an active agent. Common types of emulsions areoil-in-water, where oil is the dispersed liquid and an aqueous solution,such as water, is the dispersion medium, and water-in-oil, whereconversely, an aqueous solution is the dispersed phase. It is possiblealso to prepare emulsions that are basically non-aqueous, for example,using anionic and cationic surfactants of the non-aqueous immisciblesystem of glycerol and olive oil. An emulsion of a composition of thepresent invention can have a number of other materials that areimmiscible along with the compound of the present invention (e.g., AFC).When the composition of this invention is an emulsion including AFC,non-lipid based vehicles are preferred due to the lipophilic nature ofthe compound. Emulsifying agent carriers useful in the present inventionare described hereinabove.

In some embodiments, the compositions of the present invention can bemixed with a gel suspension (a semisolid carrier) or solid carrier toform a paste, powder, ointment, cream, lotion, hydrogel, and the like.In some such embodiments, the compositional form is an ointment. Anointment is a semi-solid preparation often intended for externalapplication to the skin. Generally, ointment bases are categorized intohydrocarbon bases (oleaginous), which may use white petrolatum as abase; adsorption bases (anhydrous), which might use hydrophilicpetrolatum or anhydrous lanolin; emulsion bases (water and oil type);and water soluble bases, which often use polyethylene glycol as anointment base.

Additional compositions of the present invention can be prepared usingtechnology readily known in the art such as described in Remington: TheScience and Practice of Pharmacy, 20^(th) ed. (Gennaro, A. R., et al.,eds.) Lippincott Williams & Wilkins: Philadelphia (2000).

In some embodiments, the composition includes the signal transductionmodulator compound in an amount that is from about 0.01% to about 50%,expressed on a % w/w compositional basis. In some embodiments, theamount of signal transduction modulator compound in the composition isfrom about 0.1% to about 20%, expressed on a % w/w compositional basis.In some embodiments, the amount of signal transduction modulatorcompound in the composition is no more than about 10%, expressed on a %w/w compositional basis. In some embodiments, the amount of signaltransduction modulator compound in the composition is from about 0.01%to about 5%, expressed on a % w/w compositional basis.

Another aspect of the present invention, is related to a method oftreating or preventing inflammation in a mammal in need thereof or forpromoting healthy joints, the methods comprising administering to themammal a pharmaceutically effective amount of a composition of thepresent invention.

As used herein the terms “pharmaceutically effective amount,” refers toany amount of a composition of the present invention that results in atherapeutic or beneficial effect following its administration to asubject. The pharmaceutical effect can be curing, minimizing,preventing, or ameliorating a condition, syndrome, injury, disease ordisorder, improving the physical appearance and aesthetics, or theeffect can any other pharmaceutical beneficial effect. The concentrationof the substance is selected so as to exert its pharmaceutical effect,but low enough to avoid significant side-effects within the scope andsound judgment of the skilled artisan. The effective amount of thecomposition can vary with the particular condition, syndrome, injury,disease or disorder being treated, prevented or promoted (e.g., healthyjoints), the age and physical condition of the mammal to whom thecomposition is being administered, the severity of the condition,injury, syndrome disease or condition, the duration of theadministration, the nature of concurrent therapy, the specific compoundof the present invention, composition or other active ingredientemployed, the particular carrier utilized, and like factors.

A skilled artisan can determine a pharmaceutically effective amount ofthe inventive compositions by determining the unit dose. As used herein,“unit dose” refers to the amount of inventive composition required toproduce a response of 50% of maximal effect (i.e., ED₅₀). The unit dosecan be assessed by extrapolating from dose-response curves derived fromin vitro or animal model test systems.

In some embodiments, the method of the present invention treats orprevents inflammation resulting from a disease, condition, syndrome,injury or disorder of an anatomical system selected from the groupconsisting of a cardiovascular system, a cerebrovascular system, adigestive system, an integumentary system, a muscular system, a nervoussystem, a reproductive system, a respiratory system, a skeletal system,an endocrine system and a urinary system.

In some embodiments, the method of the present invention treats orprevents inflammation resulting from a joint condition, inflammation ofthe airways or inflammatory bowel disease. In some embodiments, thejoint condition includes an arthritis or a joint injury. In someembodiments, the joint condition includes arthritis. In someembodiments, the joint condition includes joint injury. In someembodiments, the method for treating or preventing a joint conditioninvolves administering the composition of the present as previouslydescribed herein.

In some embodiments, the method of the present invention treats orprevents inflammation resulting from inflammation of the airways. Insome embodiments, the inflammation of the airways includes asthma orchronic pulmonary obstructive disease; asthma; or chronic obstructivepulmonary disease. In some embodiments, the method for treating orpreventing inflammation of the airways involves administering thecomposition of the present invention as previously described herein.

In some embodiments, the method of the present invention treats orprevents the inflammation resulting from inflammatory bowel disease. Insome such embodiments, the inflammatory bowel disease includesulcerative colitis and Crohn's disease; ulcerative colitis; or Crohn'sdisease. In some embodiments, the method for treating or preventinginflammatory bowel disease involves administering the composition of thepresent invention as previously described herein.

In some embodiments, the method of the present invention promoteshealthy joints. In some embodiments, the method involves administeringthe composition of the present invention as previously described herein.

In another aspect of the present invention, two or more signaltransduction modulator compounds are used in the inventive compositionto obtain a specific pharmaceutical or cosmeticeutical effect.

Without being bound by any particular theory, in some embodiments of thepresent invention, the signal transduction modulator compound acts byprevent post-translational carboxyl methylation; in some embodiments,the signal transduction modulator compound acts by inhibitingpolyisoprenyl cysteine methyltransferase.

In another aspect, the present invention relates to a kit providingcomponents for administering a composition of the present invention. Insome embodiments, the kit of the present invention has a composition ofthe present invention for parenteral administration, as previouslydescribed herein, and a needle. In some embodiments, the kit has aplurality of individual dosage units containing a parenteral compositionof the present invention, and a plurality of needles, thereby providinga quantity of the composition for administration during a regimen. Insome embodiments, the regimen includes daily, a week, two weeks, threeweeks, a month (e.g., about 28 to about 31 days). In some embodiments,administration of the composition of the present invention involves anextended regimen, which comprises a plurality of kits of the presentinvention so as to allow an extended period of administration. Anextended regimen can be a plurality of months, a year, a plurality ofyears, or a period until the inflammation decreases or ceases. In someembodiments, the regimen is lifelong (i.e., continuing through life).

The present invention described herein has both human and veterinarianutility, and can be administered to animals of the aves, reptilia, ormammalia classes. In some embodiments of the methods of the presentinvention, the composition is administered to animals selected frombirds, reptiles or mammals. In some embodiments of the methods of thepresent invention, the animal is a mammal. In some embodiments, themammal is human. In some embodiments, the mammal is nonhuman.

A further aspect of the present invention relates to a method forpreparing the previously described compositions of the presentinvention. In some embodiments, the method for preparing the compositionof the present invention includes the step of admixing at least onesignal transduction modulator or pharmaceutically acceptable saltthereof, a carrier and optionally, an additional active ingredient.

In preparing cutaneously-administered compositions of the presentinvention, (e.g., topical skin application), in order to avoidirritation, the compositions can be prepared having a pH value betweenabout 4.0 and about 7.0, preferably between about 5.0 and about 7.0,most preferably about 6.0 or substantially 6.5. In some embodiments, themethod of preparing a cutaneously-administered composition of theinvention further includes adjusting the composition by adding a pHadjusting agent until the desired p H value is achieved. In someembodiments, the method for preparing the composition of the presentinvention further includes the step of adjusting the pH of thecomposition to a pH value from about 4.0 to about 7.0; from about 5.0 toabout 7.0; from about 6.0 to about 6.5; or substantially 6.5. SuitablepH adjusting agents include, for example, but are not limited to, one ormore adipic acids, glycines, citric acids, calcium hydroxides, magnesiumaluminometasilicates, buffers, or any combination thereof. In someembodiments, the method of preparing the compositions of the presentinvention further includes adding at least one penetration enhancer orpropellant. The mixing technique utilized in the method of preparing thecomposition of the present invention can involve any one of the knowntechniques for formulating compositions. A variety of exemplaryformulation techniques that are usable in the process of the presentinvention is described, for example, in Harry's Cosmeticology, 7^(th)edition, Edited by J. B. Wilkinson, and R. J. Moore, Longman Scientific& Technical, 1982, which is incorporated herein by reference.

While the compositions discussed herein do not necessarily treat theunderlying disease state that may give rise to the inflammatory diseasesand disorders, the compositions of the present invention can be usefulfor diminishing or alleviating the inflammation. In some embodiments,the composition of the present invention treats or prevents theunderlying condition, injury, syndrome, disease or disorder as well asinflammation. In some embodiments, the composition treats or preventssubstantially inflammation, i.e., it does not also treat or prevent theunderlying condition, injury, syndrome, disorder or disease.

When a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlesscontext clearly dictates otherwise, between the upper and lower limit ofthat range and any other stated or intervening value in that statedrange is encompassed within the present invention. The upper and lowerlimits of these smaller ranges, which may be included independently inthe smaller ranges, also is encompassed within the present invention,subject to any specifically excluded limit in the stated range. When thestated range includes one or both of the limits, ranges excluding eitheror both of those included limits are included also in the presentinvention.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein also can beused in the practice or testing of the present invention, the preferredmethods and materials are now described. AU publications mentionedherein are incorporated herein by reference to disclose and describe themethods and/or materials in connection with which the publications arecited.

It must be noted that as used herein and in the appended claims, thesingular forms “a”, “and”, and “the” include plural references unlessthe context clearly dictates otherwise.

EXAMPLES OF MODELS

The following are examples of models in which to test the efficacy ofsignal transduction modulator compounds as a new class of inflammationacting compounds that can mimic the effectiveness of corticosteroids ininflammation processes without the undesirable side effects ofcorticosteroids. Such examples are not intended to limit the scope ofwhat the inventors regard as their invention nor have the inventorsintended to represent that the in models below are the only ones thatshould or could be used to test the efficacy of the present invention.

Topical Inflammation Models Example 1 Signal Transduction ModulatorCompound AFC in an Acetone Carrier Suppresses TPA-Elicited Edema in theMurine Ear Acute Contact Irritation Model

In order to assess the effects of a representative composition of thepresent invention, a composition of AFC for reducing edema in the mouseear model, an established model of dermal inflammation, was used. (SeeCarlson, R. P., et al., Modulation of mouse ear edema by cyclooxygenaseand lipoxygenase inhibitors and other pharmacologic agents. AgentsActions, 1985. 17(2): 197-204; Kuehl, F. A., Jr., et al., Role ofprostaglandin endoperoxide PGG2 in inflammatory processes. Nature, 1977.265(5590): 170-3; Trancik R J, L. N., Evaluation of topical nonsteroidalanti-inflammatory agents, in Models in Dermatology, L. Maibach, Editor.1985, Karger. pp, 35-42; and Tramposch, K. M., Skin Inflammation, in InVivo Models of Inflammation, M. L. Morgan D W, Editor. 1999, BirkhauserVerlag. pp. 179-204.)

The standard agents for initiating inflammation were the phorbol ester,tetradecanoylphorbol acetate, (TPA) and arachidonic acid (AA). TPAproduces a greater and more prolonged neutrophil infiltration responsethan AA (See Rao, T. S., et al., Comparative evaluation of arachidonicacid (AA)-and tetradecanoylphorbol acetate (TPA)-induced dermalinflammation. Inflammation, 1993.17(6): 72341.) TPA-induced inflammationis the preferred agent and was used for this example.

A. Dose Response Curve for Irritant.

A dose response range for TPA, a compound known to induce edema, wasdetermined. TPA produces an increase in edema (ear swelling) thatreaches a maximum at 6 hours.

Increasing concentrations of TPA dissolved in acetone were applied withthe aid of a micropipetter onto the right ear of each of the five 6-8week old, male Swiss Webster mice used in this analysis. Ten microliters(10 μl) were spread evenly onto the inner and outer surfaces using thepipette tip. The mice then were returned to their cages. Thecontralateral ear was treated only with acetone. After 5.5 hours, themice were sacrificed and 6 mm punches were taken from each ear andweighed. Edema response was expressed as a percent increase in thetreated ear's weight over the untreated ear. The dose response curve, aswell as an ED₅₀ value, was determined using the Lichtfield method(Lichtfield J T W. F., A simplified method of evaluating dose-effectexperiments, Journal of Pharmacology and Experimental Therapeutics,1948, 96: 99-113).

As seen in FIG. 1, the increase in ear weight depends on TPA dose from0.25 to 1.75 μg/20 μl, reaching a maximum increase of approximately 150%of the acetone-treated ear. This experiment identified doses between1.5-2.0 μg/20 μl as suitable to use in eliciting edema in future testsof anti-inflammatory agents.

B. Signal Transduction Modulator Compound AFC in an Acetone Carrier,Itself, is not an Irritant.

A range of from about 5 mg to about 32 mg AFC, a polyisoprenyl-proteininhibitor compound, was mixed with 20 μl acetone to produce an inventiveAFC composition. Each concentration was applied with the aid of amicropipetter onto the right ear of each of six mice so that 10 μl ofeach of the concentrations of the AFC inventive compositions wereapplied to an inner ear surface and 10 μl was applied to an outer earsurface of the right ear. The AFC inventive compositions were spreadevenly with a pipette tip. Each contralateral ear was treated with onlyacetone in the same manner. The mice then were returned to their cages.After 5.5 hours, mice were sacrificed and 6 mm punches were taken fromeach ear and weighed. Edema response was expressed as the percentincrease in the treated ear's weight over the untreated (acetone,vehicle only) ear.

As shown in FIG. 2, AFC in acetone alone had no effect on the edemaresponse. The AFC inventive compositions had no effect on the ear punchbiopsy weight at a dose up to about 32 mg/20 μl. AFC did not induceedema on its own at doses 60-fold greater than doses having efficacyagainst chemically-induced edema. This finding suggests an excellentsafety profile for AFC.

C. Result of AFC Inventive Composition on TPA-Induced Edema.

In order to assess the effects of the inventive composition onTPA-induced edema, 2 μg of TPA in 20 μl acetone was applied with the aidof a micropipetter onto both ears of each of 6 mice. The mice werereturned to their cages. Fifteen minutes later, increasingconcentrations of AFC in 10 μl of acetone were applied to the inside andoutside surfaces of the right ears as described above. Twentymicroliters (20 μl) of an acetone vehicle was applied similarly to theleft ear of each mouse as an internal negative control. After treatment,the mice were returned to their cages for 5.5 hours. The mice weresacrificed by cervical dislocation. The ears were immediately removed attheir base and a 6 mm diameter punch biopsy was taken from the center ofeach ear. The ear punch was weighed on an analytical balance for edemameasurements as described above. The ability of the variousconcentrations of AFC to inhibit TPA-induced edema was assessed bydetermining the difference in weight between the AFC-treated ear and theacetone (vehicle)-only treated ear over the increase in ear punch weightinduced by TPA.

When AFC was tested in this acute inflammation mouse-ear assay, AFCreduced acute chemically induced inflammation significantly. Theinventive composition reduced the TPA-induced ear weight increase in adose dependent manner (FIG. 3). The inventive composition resulted in amaximum 80% reduction in edema. The ED₅₀ of the inventive AFCcomposition was approximately 0.44 mg/20 μl for TPA-induced edemainhibition.

Example 2 AFC Inhibits TPA-Induced Neutrophil Infiltration in Mice

A. TPA induces neutrophil infiltration in mice.

Acute contact irritants such as TPA can also induce dermal infiltrationof neutrophils. This may or may not be independent of the reduction ofedema, as: 1) the maximum neutrophil response is delayed relative themaximal edema response; 2) some irritants will induce edema independentof neutrophil infiltration; and 3) some of the known anti-inflammatoryagents reduce one, but not the other. (See Rao, T. S., et al.,Comparative evaluation of arachidonic acid (AA)-and tetradecanoylphorbolacetate (TPA)-induced dermal inflammation. Inflammation, 1993, 17(6):723-41.) In this experiment, the aim was to determine if topicallyapplied AFC would affect neutrophil infiltration in response to acutetopical irritation produced by TPA.

Neutrophil-infiltration Assay: Swiss Webster male mice (n=6) weretreated with 1 μg/20 μl of TPA as described above in order to assesswhether or not TPA induced neutrophil infiltration Acetone was used as acontrol. TPA was administered as described above. The mice were returnedto their cages for 24 hrs to allow neutrophil infiltration, thensacrificed by cervical dislocation. The ears were removed immediatelyfor punch biopsy, and punches were fixed for subsequent histologicalanalysis and MPO enzymatic assay.

MPO Assay: This assay measures myeloperoxidase, (“MPO”) which ispackaged in the primary granules of mature granulocytes including theneutrophil. Thus, the amount of MPO in the ear is proportional to thenumber of infiltrating neutrophils.

MPO enzyme activity of the ears was assayed using the technique detailedby Griffiths and coworkers (1988). To conduct the assay, each ear washomogenized in 1.0 ml of cetyltrimethylammonium bromide buffer for 5 secusing a Pro 200 tissue blender (Pro Scientific, Inc., Oxford, Conn.) atsetting 5. These samples then were centrifuged for 5 minutes at 15,000rpm in a 5415 Eppendorf microcentrifuge. Triplicate 20 microliteraliquots of supernatant were added to 200 microliters of reactionmixture (1.25 ml IM Potassium Phosphate, 4.175 mg o-dianisidinedihydrochloride and 5 μl of 1% peroxide in a final volume of 25 ml).Absorbance at 450 nm then was measured at room temperature at three 60second intervals using Bio-Kinetics Reader EL 312E (Bio-TekInstruments). Activity of the homogenate, which was determined by aBradford assay (BioRad Protein Assay, BioRad Laboratories, Inc.Hercules, Calif.), was expressed as units MPO per mg tissue +/−standarderror.

Neutrophil Counting Assay: Ear punches buffered in 10% formalin in PBSat ambient temperature for a minimum of 24 hrs. were sectioned andstained with Hematoxilin & Eosin (“H&E”). The number of neutrophils,identified by their multilobular nuclei, in 6 randomly 100× magnifiedfields distributed along the length of the ear were counted manually Theresults are expressed as the average number per field for each ear.

B. AFC inhibits TPA-induced neutrophil infiltration.

Inventive AFC compositions also were used to assess efficacy in thereduction of dermal neutrophil infiltration. (See Rao, T. S., et al.,Comparative evaluation of arachidonic acid (AA)-and tetradecanoylphorbolacetate (TPA)-induced dermal inflammation. Inflammation, 1993. 17(6):723-4 for a discussion regarding the relationship between edema andneutrophil infiltration and the effect of known anti-inflammatory agentson these variables.)

Two micrograms (2 μg) of TPA in 20 μl of acetone was applied onto bothears of each mouse to induce neutrophil infiltration. After 15 minutes,varying concentrations of AFC in acetone were applied to the right earof each mouse. After 24 hours, the mice were sacrificed. The ears wereremoved and the efficacy of AFC on neutrophil infiltration was assessedby an MPO assay and histological analysis.

1. MPO Analysis

The results showed that AFC acts to reduce neutrophil infiltration in adose dependent manner when neutrophil infiltration is measured by an MPOanalysis. When AFC was tested in the Neutrophil-Infiltration Assay, itwas found to have no inflammation activity of its own. The data indicatethat AFC produced over an 80% inhibition of TPA-induced increases in MPOactivity and had an ED₅₀ of 0.065 mg/20 μl (FIG. 4).

2. Neutrophil Counts:

This histological analysis demonstrated the efficacy of AFC insuppressing dermal neutrophil infiltration in response to acute contactirritation. As seen in FIG. 5, the presence of neutrophils in the TPAalone treated ears was observed clearly at 24 hours after treatment.Essentially no neutrophils were observed in the ears that were notexposed to TPA. In the ears pretreated with TPA and then treated withvehicle or AFC, the numbers of neutrophils were comparable betweenvehicle plus TPA-treated ear and ears treated with TPA alone. Asubstantial reduction of neutrophils can be observed in the AFC treatedear.

Upon counting the neutrophils (FIG. 6), 1.0 mg/20 μl₉ of AFC produced astatistically significant 80% reduction in dermal neutrophils producedin response to acute contact irritation by TPA. (Statisticalsignificance was calculated using a Student's paired t-test).

C. The Effect of AFC on Neutrophils is Time Dependent

The effectiveness of AFC treatment at various times before and after TPAapplication was assessed using MPO as a measure of neutrophilinfiltration. In this example, both ears of six mice were treated with a1 μg/20114 dose of TPA in acetone. The right ear then was treated with 1mg/20 μl AFC inventive composition at various times before and after TAapplication, while simultaneously treating the contralateral ear withacetone.

The results show the efficacy of AFC treatment prior to, simultaneouswith, or after exposure of skin to TPA (FIG. 7). There was a gradualdecrease in MPO activity with time at which AFC was applied after TPAapplication, the steroid dexamethasone showed a similar time dependence.Thus, it can be anticipated that AFC will act like steroids in reducingestablished inflammatory conditions.

These results support a wide range of possible cosmetic andpharmaceutical applications for AFC.

Example 3 The AFC Inventive Composition does not Exhibit SystemicEffects

The effect of AFC on TPA induction of neutrophil MPO activity wascompared with two other agents representing different classes ofcommonly used anti-inflammatories that inhibit inflammation bymechanisms different from AFC. These included dexamethasone, a steroid,and indomethasone, a non-steroid anti-inflammatory drug, which targetscycloxygenases. The action of AFC in this model was, therefore, comparedto that of dexamethasone and indomethasone. Each of these agents weretested using the same protocols used to test AFC.

As shown in FIGS. 8B and 8C, when the concentration of dexamethasone andindomethasone is increased, the contralateral vehicle-treated ear showsincreasing inhibition of MPO activity, reflective of inhibition ofneutrophil infiltration. This is evidence that topically applieddexamethasome and indomethasone are entering the circulation andexerting a systemic effect with increasing effective local doses. WithAFC, no effect was seen on the vehicle-treated ear (FIG. 8A). Topicallyapplied AFC, even at its highest effective local doses is not enteringthe circulation and, therefore, has no systemic effect in the mousemodel.

Example 4 Effect of an AFC and Acetone Composition on ArachadonicAcid-Induced Edema and Arachadonic Acid-Induced Neutrophil Infiltration

Arachadonic acid (“AA”), another standard agent that is used routinelyas a contact irritant in the mouse ear model to assay the effectivenessof both steroidal and nonsteroidal anti-inflammatory agents, is themetabolic precursor for a number of lipoxygenase and cyclooxygenaseproducts. Its mechanism of action and, thus, the signaling pathways itactivates, differ from those activated by topically applied TPA. AAproduces a more rapid edema than TPA that peaks at 1 hour afterapplication. There is minimal histologically observable neutrophilinfiltration in response to AA, but an increase in MPO can be detected.Experience has shown that effectiveness against cyclooxygenase activatedinflammation in this model is less predictive of effectiveness againsthuman inflammatory diseases than effectiveness against TPA activatedinflammation.

The effect of the inventive compositions on arachidonic acid (AA)induced inflammation was assayed using the same protocols as above, butwith the following modifications. AA was applied to both ears at 4 mg/40μl acetone. The ears were harvested at 1 hour to measure edema, themaximum response time, and at 5 hours for inflammatory neutrophilinfiltration as measured by an MPO assay.

The AFC inventive composition, prepared as described above, was lesseffective in reducing granulocyte infiltration induced by AA than TPA.It has 50% of the activity of TPA and a 10 fold higher ED₅₀ (FIG. 9).

Example 5 AFC Inventive Composition Visibly Reduces TPA-Induced Erythema

For this example, both ears of a mouse were treated with a 1 μg/20 μldose of TPA in acetone. After 1 hour, the right ear was treated with 1mg/20 μl of inventive AFC composition and the left ear was treated withacetone alone. The photo was taken 23 hours later using a Nikon D70digital camera. An effect of the AFC inventive composition onTPA-induced erythema was observed (FIG. 10).

Example 6 AFC Inventive Compositions Reduce Inflammation in Humans whenPre-Applied

An irritant was applied to the middle of the upper back of a humansubject using a 0.2 ml 20% SDS solution and a Hill-Top Chamber patchwith Webril pad. AFC, at a concentration of 140 mM in aqueousformulation, was pre-applied to patch areas 1 a and 1 b (FIG. 11).Patches 1 a and 2 a were removed after 2 hours, while patches 1 b and 2b were removed after 2 hours and 30 minutes. High levels of irritationwere visible in patch sites 2 a and 2 b. Site 1 a showed normal skinwhile 1 b showed a mild response. These results show that the inventivecomposition can reduce or prevent inflammation when human skin isexposed to an irritant.

Example 7 The Effect of AFC on Chronic Irritation in Mice

The effectiveness of the inventive compositions against establishedchronic irritation can be assayed using a modification of the techniqueof Stanley P L et al., Mouse skin inflammation induced by multipletopical application 12-O-tetradeconoyphorbol-13-acetate. Skin Pharmacol.1991, 4(4):262-71. Both ears of each mouse are treated with TPA inacetone, as above, in a series of 5 applications on the mornings of days0, 2, 4, 7, and 9. The treated ear receives the inventive compositionscontaining AFC and acetone, in series of three paired applications, suchthat it is applied 6 hours apart on days 7, 8 and 9. Punches of the earsthen are taken the afternoon of the tenth day and prepared, as above,for the edema assay and the infiltration of neutrophils. Totalgranulocyte infiltration then is assayed by measuring MPO activity.Macrophage infiltration is determined immunocytologically using theMOMA-2 antibody. Hydrocortisone, which is known to reduce inflammatoryedema granulation infiltration and microphage infiltration, can be usedas a positive control. It is contemplated that the results likely willshow that AFC in acetone reduces chronic edema and neutrophil number inmice.

Example 8 The Effect of the AFC Inventive Composition on Delayed-TypeHypersensitivity

The mouse ear model, described above, can be modified to assay theeffect of anti-inflammatory agents in an immune based inflammation model(See Tramposch, K. M., Skin Inflammation, in In Vivo Models ofInflammation, M. L. Morgan D W, Editor. 1999, Birkhauser Verlag. pp.179-20 and Chapman, J. P., Z. Ruben, and G. M. Butchko, Histology of andquantitative assays for oxazolone-induced allergic contact dermatitis inmice. Am J Dermatopathol, 1986. 8(2): 130-8). In this model, asensitizing dose of dinitrofluorobenzene (DNFB) 1-3% in acetone can beapplied topically according to a modification of the method by Back etal. to the shaved bellies of mice to elicit an immune response. (SeeBack, O. and T. Egelrud, Topical glucocorticoids and suppression ofcontact sensitivity. A mouse bioassay of anti-inflammatory effects. Br JDermatol, 1985. 112(5): 539-45 and Bailey, S. C., et al., A novelcontact hypersensitivity model for rank-ordering formulatedcorticosteroids. Inflamm Res, 1995. 44 Suppl 2: S162-3.) Mice then arechallenged on day 5 with 40 μl of 0.5-1% DNFB to each ear. The AFCinventive compound is applied either 0.5 hour before or 15 min after thechallenge to one ear and the vehicle is applied to the other ear. Theears are assayed for edema or neutrophil infiltration 5 hours later.Dexamethasone is used as a positive control. Five days later, the earsare challenged topically with a dose of DNFB insufficient to producecontact irritation. Simultaneously, cell infiltration studies areinitiated. It is predicted that there initially will be more neutrophilsthan macrophages; but by 48-72 hours, macrophages will be thepredominant population. Its contemplated that no inflammatory responsewill be seen, and the inventive AFC composition is, therefore, effectivein reducing both edema and neutrophil infiltration.

Joint Inflammation Models

These models are used to show that the compounds of the presentinvention can treat or prevent joint inflammation.

Example 9 Lewis Rat Adjuvant-Induced Arthritis Model

Male Lewis rats are immunized with the adjuvant at the base of the tailon Day 0. On Day 7, 14, or 21 (or shorter or longer, depending on thestudy's goals) the rats' rear paw volume can be measured macroscopicallyby blinded observers for edema. The paws can then be amputated andx-raved for bone/joint destruction via a grading system of 0-4 calledthe “radiological index.” Such a model is employed in Yamashita, A. etal. (2002) The Journal of Immunology 168: 450-457; Zhao, H. et al.(2000) J. Orthop. Sci. 5:397; and Barbier, A., et al. (1986) Ann. Rheum.Dis. 45:67.

Example 10 Type II Collagen Induced Arthritis

Male DBA-1/BOM mice are immunized in the tail with bovine type IIcollagen that has been prepared and emulsified with an adjuvant. Afteran incubation period, the paws of the mice are inspected macroscopicallyfor edema and assigned a grade by independent, blinded observers. Thewhole joints can be removed, fixed, embedded in paraffin, sectioned, andstained for inflammatory cell infiltration. Bone and joint destruction,a characteristic of collagen-induced arthritis, can be measured as well.The collagen induced arthritis model using DBA-1/BOM mice is describedby Lubberts, E. et al. (2000) J. Clin. Invest. 105: 1697; and Lubberts,E. et al. (2003) J. Immunol. 2003: 2655-2662.

Irritable Bowel Disease Model

This model can be used to show that the compounds of the presentinvention can treat or prevent inflammation caused by irritable boweldisease.

Example 11 Acetic Acid Induced Irritable Bowel Disease in Rats

Male Sprague-Dawley rats have IBS (irritable Bowel Syndrome) induced viaintracolonic instillation of 4% acetic acid solution, and are allowed torecover for six days. On day seven, collection and measurement ofinflammation is performed. Colonic segments are removed and put undertension to simulate motor activity of intestinal circular muscles. Theeffect of a drug on the colonic motor activity is quantified bymeasuring the mean intraluminal pressure at a given concentration. Themean intraluminal pressure is calculated digitally by dividing anintegral value of pressure (area under the pressure trace) by the numberof data points (tracing time). The acetic acid induced IBS model isdescribed by La, J. H. et al. (2005) World J. Gastroenterol. 11(2):237-241.

Induced Asthma Model

This model can be used to show that the compounds of the presentinvention treat or prevent inflammation of the airways.

Example 12 Rat Lung Sensitization with OVA and Bordetella Pertussis

INBRED Brown Norway rats are sensitized with ovalbumin (OVA) adsorbed inaluminum hydroxide dissolved in phosphate-buffered saline (PBS), andheat killed Bordetella pertussis. Then the rats undergo an airwaychallenge using 5% aerosolized OVA or bovine serum albumin (BSA)delivered through orotracheal intubation using a rodent pulmonarymechanics system. The lungs then are processed via 2 mM EDTA/PBSperfusion through the right ventricle; broncho-alveolar lavage (BAL)fluid samples are collected through tracheostomy, the lungs are fixed at25 cm H₂O by tracheobronchial infusion of 4% paraformaldehyde/PBS or 10%formalin BS; and tissue sections are obtained in parahilar andmidsagittal orientation. This rat induced asthma model is described byRamos-Barbón, D., et al. (2005) J. Clin. Invest. 115: 1580-1589.

While the present invention has been described with reference to thespecific embodiments thereof, it should be understood by those skilledin the art that various changes may be made and equivalents substitutedwithout departing from the true spirit and scope of the invention. Inaddition, many modifications may be made to adopt a particularsituation, material, composition of matter, process, process step orsteps, to the objective spirit and scope of the present invention. Allsuch modifications are intended to be within the scope of the claimsappended hereto.

1. A composition for treating or preventing inflammation comprising: a.at least one signal transduction modulator compound or apharmaceutically acceptable salt thereof; b. a carrier; and c.optionally, an additional active ingredient.
 2. The compositionaccording to claim 1, wherein the composition is administered by a routeselected from oral, buccal, cutaneous, nasal, parenteral, vaginal andrectal.
 3. The composition according to claim 1, wherein the at leastone signal transduction modulator compound is selected from the groupconsisting of: a. a compound of Formula (I) or a pharmaceuticallyacceptable salt of Formula (I):

wherein: R¹ is a C₁-C₃ alkyl; R² is —COX, wherein X is —OH, —OCH₃, —NH₂,—NHR⁴, —N(R⁴)₂, or a halogen; R³ is a C₁₀-C₂₅ alkyl or a C₁₀-C₂₅ alkene;and R⁴ is a C₁-C₃ alkyl; b. when R² is —COOH, a pharmaceuticallyacceptable salt of Formula (I) selected from the group consisting of analkali metal salt, alkaline earth metal salt, ammonium salt, andsubstituted ammonium salt; c. a compound of Formula (II) or apharmaceutically acceptable salt of Formula (II):W—Y-Q-Z  (II) wherein: W is a farnesyl group, geranylgeranyl group,substituted farnesyl group or substituted geranylgeranyl group; Y is—S—, —O—, —Se—, —SO—,

—SeO—, —SO₂—, or —SeO₂—; and Q is

wherein: n, n′ and n″=1, 2, 3, 4, 5, or 6; T_(1′), T_(1″), T_(n∝) andT_(n″) are each, independently, H, F, Br, —NHCOCH₃, —NH₂, a peptide, analkane group, an alkene group, an polyethyleneglycol group, a saturatedfatty acid, an unsaturated fatty acid, a monosaccharide, or adisaccharide; Z is —CN, —CONH₂, —NO₂, —COOH or salts and esters thereof,—PO₃ or salts or esters thereof or —SO₃ or salts or esters thereof;provided that when W is farnesyl, Y is —S—, n is 2, and either T_(2′),or T_(2″) is —NHCOCH₃, then Z is not —COOH; d. a compound of Formula(III) or a pharmaceutically acceptable salt of Formula (III):W—Y-Z  (III) wherein W, Y, and Z are as previously defined; e. acompound of Formula (IV) or a pharmaceutically acceptable salt ofFormula (IV)

wherein: Z is C—R₁₂ or N; X is —O—, —S—, —SO—, —SO₂—, —NH—, or —Se—; R⁷is a C₁₀-C₂₅ alkyl or a C₁₀-C₂₅ alkene; R⁸ is H, CN, COOR¹³, SO₃R¹³,CONR¹³R¹⁴, or SO₂N(R¹³)₂, wherein R¹³ and R¹⁴ are each, independently,hydrogen, alkyl, alkenyl, —COOM or —SO₃ M, wherein M is a cation; andR⁹, R¹⁰, R¹¹ and R¹² are each, independently, hydrogen, carboxyl, alkyl,alkenyl, aminoalkyl, nitroalkyl, nitro, halogen, amino, mono-alkylamino,di-alkylamino, mercapto, mercaptoalkyl, azido, or thiocyanato; f. thequaternary ammonium salts or N-oxides of Formula (I), wherein Z is N; g.a compound of Formula (V) or a pharmaceutically acceptable salt ofFormula (V):

wherein: Z is geranyl, farensyl, geranylgeranyl, phytyl or3,7-dimethyloctyl; R¹⁵ is butane, butene, methylbutene, CF₃, CF₃CF₂,CF₃CH₂, CHBr₂,

h. a compound of Formula (VI) or a pharmaceutically acceptable salt ofFormula (VI):

wherein: R¹⁷ and R¹⁸ are each independently H, CH₃, OCH₃, CN, NO₂ orhalogen; and R¹⁹ is H or halogen; i. a compound of Formula (VII) or apharmaceutically acceptable salt of Formula (VII):

wherein: R¹⁷, R¹⁸ and R¹⁹ are as previously defined; j. a compound ofFormula (VIII) or a pharmaceutically acceptable salt of Formula (VIII):

k. a compound of Formula (IX) or a pharmaceutically acceptable salt ofFormula (IX):

l. a compound of Formula (X) or a pharmaceutically acceptable salt ofFormula (X):

m. a compound of Formula (XI) or a pharmaceutically acceptable salt ofFormula (XI):

wherein: X is 3,7-dimethyloctyl, 3,7-dimethylhexadecene, geranyl,geranylgeranyl or farnesyl; and X′ is propene, 2-methylbutene ortriphenylmethane.
 4. The composition according to claim 1, wherein theat least one signal transduction modulator compound is selected from thegroup consisting of: a. N-acetyl-S-farnesylcysteine; b.3-farnesylhomocysteine; c. N-acetyl-S-oxo-farnesylcysteine; d.3-farnesylthio-trans-acrylic acid; e. 3-farnesylthio-cis-acrylic acid; f3-farnesyloxypropionic acid; g. 3-farnesylthiobutyric acid; h2-farnesylthioacetic acid sulfoxide; i. 3-farnesylthiopropionamide; j.2-methyl-3-farnestylthiopropionic acid; k. 2-farnesylthio-1-nitroethane;l. 2-farnesylthio-S-methyl acetothiohydroximate; m.3-farnesylthio-2-methylenepropionic methyl ester, n. S-farnesylcysteine;o. N-acetylgeranylgeranylcysteine; p. 3-farnesylthio-2-nitropropane; q.3-farnesylthio-2-methylenepropionic acid; r.N-benzoyl-5-farnesylcysteine; s. disodium 2-farnesylthioethyl phosphate;t. 3-farnesylthiopropionitrile N-acetyl-Se-farnesyl-D,L-cysteine; u.N-acetyl-S-farnesyl-D-cysteine; v. 3-farnesylselenopropionic acid; w.N-acetyl-S-geranyl-L-cysteine; x. 3-farnesylthiononanoic acid; y.3-farnesylthiocyclohexanecarboxylic acid; z. farnesyl-thiosalicyclicacid; aa. 2-chloro-5-farnesylaminobenzoic acid; bb. farnesylthionicoatinic acid; cc. 5-fluoro-farnesyl-thiosalicyclic acid; dd.5-chloro-farnesyl-thiosalicyclic acid; ee.4-chloro-farnesyl-thiosalicyclic acid; ff.S-farnesyl-methylthiosalicylic acid; gg. N-Fmoc-S-farnesyl-cysteine; hh.N-Boc-S-farnesyl-cysteine; ii. N-phthaloyl-5-farnesyl-cysteine; and apharmaceutically acceptable salt thereof.
 5. The composition accordingto claim 1, wherein the at least one signal transduction modulatorcompound is N-acetyl farnesyl-cysteine orN-acetylgeranylgeranylcysteine.
 6. The composition according to claim 1,wherein the at least one signal transduction modulator compound isN-acetyl farnesyl-cysteine.
 7. The composition according to claim 1,wherein the signal transduction modulator comprises N-acetylfarnesyl-cysteine and N-acetylgeranylgeranylcysteine.
 8. The compositionaccording to claim 1 further comprising at least one penetrationenhancer or propellant.
 9. The composition according to claim 1, whereinthe inflammation is associated with a joint condition, an inflammationof the airways, or an inflammatory bowel disease.
 10. The compositionaccording to claim 9, wherein the joint condition comprises an arthritisor a joint injury.
 11. The composition according to claim 9, wherein theinflammation of the airways comprises an asthma or chronic obstructivepulmonary disease.
 12. The composition according to claim 11, whereinthe asthma is chronic.
 13. The composition according to claim 11,wherein the chronic obstructive pulmonary disease comprises chronicbronchitis and emphysema.
 14. The composition according to claim 13,wherein the chronic obstructive pulmonary disease comprises chronicbronchitis.
 15. The composition according to claim 9, wherein theinflammatory bowel disease comprises ulcerative colitis and Crohn'sdisease.
 16. The composition according to claim 15, wherein theinflammatory bowel disease comprises ulcerative colitis.
 17. Thecomposition according to claim 15, wherein the inflammatory boweldisease comprises Crohn's disease.
 18. The composition according toclaim 10, wherein the composition is administered by a route selectedfrom the group consisting of oral, cutaneous and parenteral.
 19. Thecomposition according to claim 11, wherein the composition isadministered by a route selected from the group consisting of oral andparenteral.
 20. The composition according to claim 15, wherein thecomposition is administered by a route selected from the groupconsisting of oral, parenteral and rectal.
 21. A composition forpromoting healthy joints comprising: a. at least one signal transductionmodulator compound or a pharmaceutically acceptable salt thereof b. acarrier; and c. optionally, an additional active ingredient.
 22. Thecomposition according to claim 1, wherein the at least one signaltransduction modulator compound is contained within a botanical extract.23. The composition according to claim 1, wherein the at least onesignal transduction modulator compound is contained within a microbialextract.
 24. The composition according to claim 1, wherein the optionaladditional active ingredient is selected from a group consisting of aprotective agent, a demulcent, an emollient, an astringent, a steroidalanti-inflammatory agent, a non-steroidal anti-inflammatory agent, anantioxidant, a chemotherapeutic agent, an antihistamine agent and acleansing agent.
 25. The composition according to claim 1, wherein thecomposition comprises a mixture selected from the group consisting of asolution, an emulsion, a suspension and a powder.
 26. The compositionaccording to claim 1, wherein the signal transduction modulator compoundcomprises from about 0.01% to about 50% w/w of the composition.
 27. Thecomposition according to claim 1, wherein the signal transductionmodulator compound comprises from about 0.01% to about 5% w/w of thecomposition.
 28. A method of treating or preventing inflammation in amammal in need thereof the method comprising administering to the mammala pharmaceutically effective amount of a composition comprising: a. atleast one signal transduction modulator compound or a pharmaceuticallyacceptable salt thereof; b. a carrier, and c. optionally, an additionalactive ingredient.
 29. The method according to claim 28, wherein theinflammation is associated with a joint condition, an inflammation ofthe airways or an inflammatory bowel disease.
 30. The method accordingto claim 29, wherein the joint condition comprises an arthritis or ajoint injury.
 31. The method according to claim 30, wherein thecomposition further comprises a penetration enhancer.
 32. The methodaccording to claim 29, wherein the inflammation of the airways comprisesan asthma or a chronic pulmonary obstructive disease.
 33. The methodaccording to claim 29, wherein the inflammation is associated with aninflammatory bowel disease.
 34. The method according to claim 28,wherein the composition is administered by a route that is oral, buccal,parenteral, nasal, vaginal or rectal.
 35. A method of promoting healthyjoints in a mammal in need thereof, the method comprising administeringto the mammal a pharmaceutically effective amount of a composition fortreating inflammation comprising: a. at least one signal transductionmodulator compound or a pharmaceutically acceptable salt thereof; b. acarrier; and c. optionally, an additional active ingredient.
 36. A kitcomprising a composition for treating or preventing inflammation or forpromoting healthy joints, the kit comprising: a. a compositioncomprising: i. at least one signal transduction modulator compound or apharmaceutically acceptable salt thereof; ii. a carrier, and iii.optionally, an additional active ingredient; and b. a needle.
 37. Thekit according to claim 36 further comprising a plurality of individualdosage units of the composition and a plurality of needles.
 38. The kitaccording to claim 37, wherein the plurality of individual dosage unitsand the plurality of needles provides for an administration regimenselected from the group consisting of daily, weekly or monthly.